Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (220 mg) in dichloromethane (7 mL) at room temperature was added triethylamine (0.174 mL) and then 3-chloropropane sulfonyl chloride (0.134 mL). The reaction mixture was stirred at room temperature for 30 min and then quenched with water (25 mL) and extracted into dichloromethane (3×25 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 3-chloro-propane-1-sulfonic acid (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amide (301 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g 5-tert-butyl-2-methoxy-benzoic acid are dissolved in 15 ml sulphuric acid, cooled to 0° C. and combined dropwise with a solution of 2.3 ml nitric acid in 2.6 ml sulphuric acid. The mixture is stirred for 1.5 hours at 0° C. and for 1 hour at ambient temperature. Then it is added to ice water. The precipitate is filtered off, taken up in dichloromethane and dried on magnesium sulphate. The solvent is eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].[K+].C1(C)C=CC(S(O[CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=1>CS(C)=O>[CH:33]1([N:11]2[C:12]3[C:17]4[C:9]([CH2:8][C@@H:7]5[C@@H:6]([C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3][N:2]5[CH3:1])=[CH:10]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CC(C(=O)O)C[C@@H]2c3cccc4c3c(cn4C3CCCC3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To a 500 ml, three-neck round bottom flask was added 10.0 g (33.9 mmol) of 92% pure 9,10-dihydrolysergic acid, 11.72 g (180.0 mmol) of 86% pure powdered potassium hydroxide and 150 ml of DMSO. The mixture was stirred for 15 minutes and 10.22 g (42.6 mmol) of p-toluenesulfonic acid, cyclopentyl ester was added. The mixture was stirred at room temperature for about 20 hours and an additional 3.11 g (13.0 mmol) of p-toluenesulfonic acid, cyclopentyl ester was added. The mixture was stirred for an additional two hours and was poured into 750 ml of ice water. The mixture was washed twice with 200 ml portions of ethyl acetate and the pH of the aqueous phase was lowered to about 5 with glacial acetic acid. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The solid was washed with water and dried under vacuum to provide 10.05 g of the title compound having a purity of 96.3 %. Yield 85.2%. Exact mass: theory 339.20725; found 339.20633.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([CH3:6])[CH:4]=O.[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH3:6][C:3]1[CH:2]=[N:1][C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:4]=1
Reactant: O=C1CCCCC1
Reactant: CC(C=O)=CN
Product: Cc1cnc2c(c1)CCCC2
Yield: 30 %

Procedure:
The title compound was prepared from commercially available 3-amino-2-methylacrolein and cyclohexanone according to the method of Breitmaier and Bayer (Tet. Letts, 1970, 38, 3291-4) and isolated as a pale yellow oil b.p. 120°/15 mm. (30% yield).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:22]2[CH:23]=[N:24][CH:25]=[CH:17][C:18]=2[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Oc2ccccc2)cc1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 4-phenoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.42 (br s, 1H), 8.18 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.35-7.40 (m, 4H), 7.13 (t, 1H, J=7.2), 6.97-7.02 (m, 4H), 4.55 (s, 2H). [M+H] calc'd for C19H16N2O3, 321; found 321.
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]([OH: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].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH2:63].FC(F)(F)S(O)(=O)=O>>[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]([O:50][CH2:63][CH:62]=[CH2:61])[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(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-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 (200 mg in 3.0 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (88 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 18 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (156 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20]O)[N:18]=3)=[CH:10][CH:9]=2)[N:3]=[CH:2]1.Cl.[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:20][CH2:19][C:17]1[N:18]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[CH:13][CH:12]=2)[O:15][CH:16]=1
Reactant: OCCc1coc(-c2ccc(OCc3cscn3)cc2)n1
Reactant: C[C@@H]1CCCN1
Agent: Cl
Product: C[C@@H]1CCCN1CCc1coc(-c2ccc(OCc3cscn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Example 53 from 2-{2-[4-(Thiazol-4-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol (See Intermediate 68) and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 370.2 (M+1)
Reaction SMILES: [C:1]1([CH2:7][C:8]([C@H:10]2[C@@H:14]([C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)C(=O)[N:11]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[C:44](=[O:47])([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH2:24]([N:13]1[C:14]2=[C:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:9][C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:10]2[N:11]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:44]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1ccccc1)[C@@H]1[C@H](C(=O)Cc2ccccc2)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1n(Cc2ccccc2)c2c(Cc3ccccc3)oc(Cc3ccccc3)c2n1Cc1ccccc1
Yield: 76 %

Procedure:
A solution of (4R-cis)-4,5-bis(phenylacetyl)-1,3-bis(benzyl)-2-imidazolidinone (79 mg, 0.16 mmol) and ammonium acetate (25 mg, 0.32 mmol) in acetic acid (2 ml) was refluxed 18 hours. The solution was neutralized with solid potassium carbonate and partitioned between EtOAc/water. The aqueous phase was washed twice with EtOAc. All organic extracts were combined and dried over MgSO4, then concentrated to a brown oil. Further purification was achieved by preparative TLC (silica gel, 30% EtOAc/hexane) to give the product as a yellow-brown oil, (59 mg, 76% yield). 1HNMR (CDCl3) δ7.10-7.44 (m, 10H), 4.99-5.16 (m, 2H) , 4.17-4.29 (m, 3H), 3.59 (d, 1H), 2.54 (m, 1H), 2.07-2.33 (m, 3H), 1.21-1.50 (m, 6H), 0.84-0.93 (m, 6H). MS: 417 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.Cl.[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49][NH2:50]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:50][CH2:49][C:40]1[CH:41]=[CH:42][C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:39]=1)=[O:25]
Reactant: NCc1ccc2ccccc2n1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccc3ccccc3n2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-quinolin-2-yl-methylamine dihydrochloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:41])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([NH:39][CH3:40])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([NH:39][CH3:40])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:41])[NH:16][C:9]=2[CH:10]=1
Reactant: CNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CNc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-[3-(6-methylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K54) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (132 mg).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](=O)([O-])[O-].[K+].[K+]>[Cl-].C[N+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([O:4][CH3:22])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C([O-])[O-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 99 %

Procedure:
Morphine of 70% purity 407 parts (1 mole part), potassium carbonate 552 parts (4 moles part) and trimethylphenyl-ammonium chloride 188 parts (1.1 moles part) are heated under stirring in toluene (4000 parts) at 45° to 120° C. for 2-5 hrs. to yield 296 parts codeine (99% yield), after workup as in Example 1.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH3:8][Si:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][OH:12]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[O:6]=[C:5]([O:12][CH2:11][CH2:10][Si:9]([CH3:14])([CH3:13])[CH3:8])[CH2:4][CH2:3][C:2]([OH:7])=[O:1]
Reactant: C[Si](C)(C)CCO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)CCC(=O)O
Temperature: 25 °C
Yield: 118 %

Procedure:
Dihydrofuran-2,5-dione (8.0 g, 80 mmol) and 2-(trimethylsilyl)ethanol (5 g, 42.3 mmol) were dissolved in dry toluene (80 mL), followed by addition of DMAP (0.517 g, 4.23 mmol). The mixture was heated to reflux for 14 h. The mixture was cooled to rt, diluted with EtOAc (50 mL) and washed with aq. HCl (1 N, 3×30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude product as a white semi-solid (10.9 g, purity 85% as determined by 1H NMR, 100% yield), which is used in next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[C:9]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:8]=2)(=[O:3])C.Cl[O-:22]>O1CCOCC1>[CH:15]1([C:9]2[CH:8]=[C:7]3[C:12]([C:13]([OH:14])=[C:4]([C:1]([OH:22])=[O:3])[CH:5]=[N:6]3)=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)c1cnc2cc(C3CCCCC3)ccc2c1O
Reactant: [O-]Cl
Solvent: C1COCCO1
Product: O=C(O)c1cnc2cc(C3CCCCC3)ccc2c1O
Reaction time: 0.75 h

Procedure:
10 g of powdered 3-acetyl-4-hydroxy-7-cyclohexylquinoline are added to a solution of 10 ml of dioxane and 10 g of a freshly prepared hypochlorite solution at room temperature. After 45 minutes, the unconverted acetyl compound is washed out with chloroform. The aqueous solution is acidified with 10% strength hydrochloric acid. The product which precipitates is washed with water and then dried. 7-Cyclohexyl-4-hydroxy-quinoline-3-carboxylic acid of melting point 241°-43°C is obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]=[CH:7]1)[CH3:5])[CH3:2].CN(CCN(C)C)C.C([Li])CCC.CON(C)[C:42](=[O:47])[C:43]([F:46])([F:45])[F:44]>C1COCC1.C(OCC)C>[CH2:1]([O:3][CH:4]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]=[C:7]1[C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])[CH3:5])[CH3:2]
Reactant: CON(C)C(=O)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)n1c(C(=O)C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(1-Ethoxyethyl)-4-(4-fluorophenyl)-5-[4-(methyl-thio)phenyl]-1H-imidazole (Example 83 Step 1) (403.8 mg; 1.04 mmol) and TMEDA (582.7 mg; 5.01 mmol) in 6 ml of THF at −78° C. was added 1.23 ml of 2.5 M n-butyllithium in hexanes. After stirring for 15 minutes, a solution of N-methoxy-N-methyltrifluoracetamide, (167 mg; 1.41 mmol) in 1 ml of THF was added. The solution was warmed to 25° C. over one hour. The reaction was diluted with diethyl ether and washed with a saturated, aqueous, solution of sodium bicarbonate. The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography (SiO2; 25% ethyl acetate/hexane) to give 81 mg of 1-[1-(1-ethoxyethyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1H-imidazol-2-yl]-2,2,2-trifluoroethanone which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]#[N:22]>CC(C)=O>[C:21]([CH2:20][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])#[N:22]
Reactant: N#CCBr
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (2 g, 0.012 mole) and potassium carbonate (1.64 g, 0.012 mole) in acetone (10 ml) was treated with bromoacetonitrile (0.19 ml, 0.013 mole) in acetone (10 ml) and stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and the residue treated with 10% NaOH solution, then extracted with ethyl acetate. The organic extract was dried (Na2SO4) and evaporated in vacuo to give the title compound (2.35 g, 96%).
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[C:1]=[S:2]
Reactant: S=C=S
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)Cc1ccc(CSCCN=C=S)o1
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A solution of carbon disulphide (4.2 g) in dry acetone (8 ml) was added dropwise to a solution of 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (10.71 g) in dry acetone (30 ml) during 15 minutes at -10° to 0°. To the stirred solution at -15° was added dropwise a solution of mercuric chloride (13.6 g) in dry acetone (20 ml) during 45 minutes. The solution was warmed to 0° and triethylamine (11.5 g) was added dropwise with stirring during 15 minutes. The mixture was refluxed for 45 minutes, the suspension filtered and the filtrate evaporated to dryness. The oily residue was dissolved in ether (150 ml), decolourising charcoal and excess anhydrous sodium sulphate were added and the suspension filtered after 2 hours. The filtrate was evaporated to dryness, the oily residue dissolved in ether and the solution chromatographed (alumina deactivated with water, 72.5 ml/kg/ether). The appropriate eluate was evaporated to give the title compound (5.05 g) as a brown oil.
Reaction SMILES: [C:1]1([C:7]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:8][CH2:9][C@@H:10]2[O:16][C@H:15]([CH2:17][O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:13]([OH:14])[C@@H:11]2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CO>CN(C)C=O>[C:53]1([CH2:52][O:14][C@H:13]2[C@H:11]([O:12][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@@H:10]([CH2:9][O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:16][C@H:15]2[CH2:17][O:18][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: BrCc1ccccc1
Reactant: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(CO[C@H]2[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 165.7 %

Procedure:
A solution of 800 mg of 2,5-anhydro-1,6-bis-O-(triphenylmethyl)-D-glucitol in 16 ml of dry dimethylformamide was treated with 240 mg of freshly washed sodium hydride. The mixture was stirred 1.5 hours, then 1.30 g of benzyl bromide was added and stirring continued for 2.5 days. Methanol was added, the solvents removed in vacuo and the residue taken up in chloroform/water. The organic layer was washed with water and brine, then dried and evaporated, giving a yellow oil which was flash chromatographed, eluting with hexane:ethyl acetate (12:1), giving 847 mg of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9](OCC)=O)=[O:7])([O-:3])=[O:2].ClC[CH2:20][OH:21].[OH-].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O>[OH:21][CH2:20][CH2:9][CH2:8][C:6]([C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2])=[O:7]
Reactant: OCCCl
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCO)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(o-nitrobenzoyl)acetate (11.9 g, 0.05 mol), 2-chloroethanol (8 g, 0.1 mol), 50% sodium hydroxide solution (8.8 g, 4.4 g real, 0.11 mol) and 40% benzyltrimethylammonium hydroxide solution (4.2 PG,12 g, 1.7 g, real, 0.01 mol) in water (50 mL) is heated at 50°-65° C. for 4-8 hours, cooled and extracted with methylene chloride. The combined organic extracts are concentrated in vacuo to give the title product, identified by 1HNMR and 13CNMR analyses.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH:12]=[C:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)[CH3:2]>C1COCC1.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(C=C(C)C)c(C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(CC(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.4 %

Procedure:
5-Methyl-6-(2-methyl-propenyl)-nicotinic acid ethyl ester (3.98 g, 18.2 mmol) is dissolved in THF (100 mL) and MeOH (100 mL), Pd/C (500 mg, 10% Pd) is added and the mixture is stirred under 1 atm H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated to give 6-isobutyl-5-methyl-nicotinic acid ethyl ester (3.76 g) as a colourless oil; LC-MS: tR=0.75 min; [M+1]+=222.15; 1H NMR (CDCl3) δ 0.97 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.3 Hz, 3H), 2.20 (hept, J=6.8 Hz, 1H), 2.38 (s, 3H), 2.75 (d, J=7.0 Hz, 2H), 4.41 (q, J=7.3 Hz, 2H), 8.03 (d, J=1.8 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).