Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25]C(=O)C)[CH:20]=1)[CH3:4]>CO.C(OCC)(=O)C.O>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1)[CH3:4]
Reactant: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 75 °C
Yield: 87 %

Procedure:
A 2 M sodium hydroxide solution (20 mL) was added to a solution of N-(4-((6-(2-ethoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 24-6 (2.5 g, 7.04 mmol) in methanol (20 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred under reflux at 75° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature and then diluted with ethyl acetate and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=1:9-0:1-ethyl acetate:methanol=49:1-24:1) to obtain the title compound (1.92 g, 87%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([CH:21]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][CH:25]=1)[CH3:20]>O1CCCC1>[CH2:19]([CH:21]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[CH:28][CH:29]=1)[CH3:20]
Reactant: CCCCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(OCC(CC)CCCC)cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 64.5 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 13.2 mL, 13.2 mmol) was added to a stirred solution of [4-(2-ethylhexyloxy)phenylethynyl]trimethylsilane (3) (2.59 g, 13.2 mmol) in tetrahydrofuran (70 mL) and the solution stirred under nitrogen at room temperature for 100 min. The solvent was removed and the residue passed through a plug of silica with dichloromethane—light petroleum (1:9) as eluent to give 1-(2-ethylhexyloxy)-4-ethynylbenzene (4) (1.96 g, 99%) as a pale yellow-brown oil. (Found: C, 83.4, H, 9.85, C19H30OSi requires C, 83.4; H, 9.6%); νmax(film)/cm−1 3294 and 3317 (C≡C—H) and 2107 (C≡C); δH(400 MHz, CDCl3) 0.94 (6 H, m, CH3), 1.28-1.57 (8 H, m, CHCH2CH2CH2CH3 and CHCH2CH3), 1.74 (1H, m, OCH2CH), 3.01 (1 H, s, CCH), 3.85 (2 H, d, J 5, OCH2CH), and 6.85 and 7.43 (4 H, AA′BB′, phenyl H); δc(100.6 MHz, CDCl3) 11.1, 14.1, 23.0, 23.8, 29.0, 30.4, 39.3, 70.5, 75.6, 83.8, 113.7, 114.4, 133.5, 159.8.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-fluorobenzenesulfonyl chloride (380 μl). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg).
Reaction SMILES: [CH3:1][C:2]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20][C:19]2[CH:21]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][CH:13]=[CH:12][CH2:11][C:10]2=[CH:22][C:6](=[CH:7][C:8]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[N:9]2)[CH2:5][O:4][C:3]1=[O:29]>C1COCC1.[Pd]>[CH3:1][C:2]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20][C:19]2[CH:21]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:22][C:6](=[CH:7][C:8]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[N:9]2)[CH2:5][O:4][C:3]1=[O:29]
Reactant: CN(c1cc2cc(n1)CC=CCc1cccc(c1)CC(C)(NC(=O)OC(C)(C)C)C(=O)OC2)S(C)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(c1cc2cc(n1)CCCCc1cccc(c1)CC(C)(NC(=O)OC(C)(C)C)C(=O)OC2)S(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(3EZ)-14-methyl-8-[methyl(methylsulfonyl)amino]-13-oxo-12-oxa-7-azatricyclo[14.3.1.16,10]henicosa-1(20),3,6(21),7,9,16,18-heptaen-14-yl]carbamate (22.5 mg, 0.042 mmol) (Intermediate V.11.c.1) in degassed THF (2.5 mL) was added palladium on carbon (10%, 3 mg). The reaction was stirred under a hydrogen atmosphere (1 atm) for 1 h and filtered through celite. Concentration gave tert-butyl [14-methyl-8-[methyl(methylsulfonyl)amino]-13-oxo-12-oxa-7-azatricyclo[14.3.1.16,10]henicosa-1(20),6(21),7,9,16,18-hexaen-14-yl]carbamate. MS: 532.0 (M+1) ES+
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:11][CH2:12][CH3:13])(=[O:10])[C:7]([CH3:9])=O.Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:7]([C:6]([O:11][CH2:12][CH3:13])=[O:10])=[CH:9]2
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 500 ml flask, 14 g of 4-bromophenylhydrazine hydrochloride was dissolved in 170 ml of ethanol, and 1.2 ml of sulfuric acid and 8.5 ml of ethyl pyruvate were added. The reaction mixture was stirred for about 2 hours at room temperature and evaporated under reduced pressure to dryness. To the residue was added 23 ml of polyphosphoric acid, and the resulting solution was then stirred for 2 hours at 100° C.-110° C. After water was added, the reaction solution was neutralized with saturated aqueous NaHCO3 solution and then extracted to times with ethyl acetate. The extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(9:1)] to obtain 10 g of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.C[O-].[Na+].[N:19](OCCCC)=[O:20]>>[OH:20][N:19]=[C:10]([C:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH:8]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCCON=O
Reactant: COC(=O)Cc1csc2ccc(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(=NO)c1csc2ccc(Cl)cc12

Procedure:
Reaction of chloroacetone with 4-chlorothiophenol gave (4-chlorophenyl)thiomethyl methyl ketone, which was cyclized by reaction with polyphosphoric acid to 5-chloro-3-methylbenzothiophene. Bromination of the latter compound by photochemical reaction with N-bromosuccinimide provided 5-chloro-3-bromomethylbenzothiophene, which was reacted with sodium cyanide to give 5-chloro-3-cyanomethylbenzothiophene. The latter compound was hydrolyzed and esterified to give methyl α-(5-chloro-3-benzothienyl)acetate. Reaction of the ester with sodium methoxide and n-butyl nitrite afforded methyl α-hydroxyimino-α-(5-chloro-3-benzothienyl)acetate. Reduction of the oxime by reaction with zinc and formic acid and subsequent reaction with di-tert.-butyl carbonate gave N-tert.-butoxycarbonyl-(5-chloro-3-benzothienyl)glycine. NMR (CDCl3): δ 1.1-1.5 (broad s, 9H); δ 5.4-5.7 (broad s, 1H); δ 7.2-8.0 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]([C:42]1[C:47]([C:48]([O:50]CC)=[O:49])=[CH:46][CH:45]=[C:44]([C:53]([F:56])([F:55])[F:54])[N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH2:1]([N:4]([C:42]1[C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=[C:44]([C:53]([F:54])([F:55])[F:56])[N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C(F)(F)F)ccc1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(C(F)(F)F)ccc1C(=O)O

Procedure:
Ethyl 6-trifluoromethylpyridin-2-one-3-carboxylate, prepared by the method described in Helv. Chim. Acta. 71, 596 (1988), is chlorinated with phosphorus oxychloride to give the 2-chloro compound. Treatment of ethyl 2-chloro-6-trifluoromethylpyridine-3-carboxylate with N-triphenylmethyl-5-[2-(4'-propylaminomethyl-biphenyl)]tetrazole, prepared as described in Example 72B, in tetrahydrofuran containing triethylamine affords the tertiary amine. Treatment of ethyl 2-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-6-trifluoromethyl-pyridine-3-carboxylate with p-toluenesulfonic acid monohydrate in methanol to detritylate followed by sodium hydroxide in methanol hydrolysis gives the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:34][C:6]1[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10](=[O:27])[N:11]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.089 mmol), β-alanine (635 mg, 7.13 mmol) and NaOMe solution (10.7 mL, 5.35 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 6 mg of the title compound as a white solid. MS: (+) m/z 507.49 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cc(C=O)ccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2c(ccn2C)c1
Reaction time: 3 h
Yield: 45 %

Procedure:
1-Methyl-1H-indole-5-carbaldehyde (338 mg, 2.13 mmol) was dissolved in anhydrous methanol (10 ml). Methylamine (0.80 ml of 33% solution in ethanol, 6.43 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a brown oil and then dissolved in anhydrous methanol (10 ml). Sodium borohydride (83.0 mg, 2.19 mmol) was added and the mixture was stirred overnight at room temperature. Water (4 ml) was added and the solution was concentrated. Sodium hydroxide (8 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford methyl-(1-methyl-1H-indol-5-ylmethyl)-amine (167 mg, 45%) as an orange oil: 1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.261 (d, J=3.2 Hz, 1H), 7.11 (d, J=12.0 Hz, 1H), 6.345 (d, J=4.0 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]2[S:25][C:20]3=[N:21][CH:22]=[CH:23][N:24]=[C:19]3[CH:18]=2)=[O:16])[CH:13]=1)=[O:6].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:26][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:27]=[CH:28][N:29]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:3]=2)=[CH:13][C:12]=1[NH:14][C:15]([C:17]1[S:25][C:20]2=[N:21][CH:22]=[CH:23][N:24]=[C:19]2[CH:18]=1)=[O:16]
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Br)c2)cc1NC(=O)c1cc2nccnc2s1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 30 (25 mg, 0.053 mmol) in pyrrolidine (0.5 mL) was heated at 80° C. overnight. Quenched in 3% citric acid solution and extracted with CH2Cl2 (2×). The combined organic layers were dried with Na2SO4 and concentrated in vacuo. Purification by chromatography CH2Cl2/MeOH (97/3) and triturating with acetonitrile gave the title compound N-(2-methyl-5-(2-(pyrrolidin-1-yl)isonicotinamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 31b (10.7 mg, 44%). NMR (400 MHz, DMSO-d6) 1.97 (m, 4H), 2.26 (s, 3H), 3.45 (m, 4H), 6.88 (s, 1H), 6.98 (dd, J=5.1 and 1.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.23 and 1.6 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.1 Hz, 1H), 8.53 (br s, 1H), 8.75 (d, J=2.3 Hz, 1H), 8.88 (d, J=2.3 Hz, 1H), 10.33 (s, 1H), 10.52 (s, 1H). (m/z)=459 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M98) (0.27 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (120 mg, 57%).
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:8][CH2:7]2)[OH:5])[CH2:3][CH2:2]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:13][C@@H:14]1[O:16][CH2:15]1)(=O)=O.[H-].[Na+].CS(C)=O>O1CCCC1.O>[CH:1]1([CH:4]([CH:6]2[CH2:8][CH2:7]2)[O:5][CH2:13][C@H:14]2[CH2:15][O:16]2)[CH2:3][CH2:2]1
Reactant: OC(C1CC1)C1CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C1CC1C(OC[C@H]1CO1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Dicyclopropylmethanol (880 mg) obtained in Step 1 and (R)-glycidyl nosylate (3.05 g) were dissolved in tetrahydrofuran (7.3 ml), sodium hydride (471 mg) and dimethyl sulfoxide (1.5 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to give the title compound (760 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:30]>>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[NH:30])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1
Reactant: N
Product: N=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ncccc1OCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (1.26g, 0.006 mol), N-[3-(2-chloro-6 fluorobenzyloxy)pyrid-2-yl]-N'-(4-nitrophenyl)thiourea (2.08g, 0.005 mol) and methanolic ammonia solution (40 ml) was stirred for 24 hours at room temperature, then heated under reflux for 30 min. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from ethanol gave the desired product. Yield 1.16 g (58%), m.p 180°-182 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:12].C[Si](C)(C)N[Si](C)(C)C.[K].C[O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=[O:24]
Reactant: COC(=O)c1cccc(C)n1
Reactant: Cc1ccnc2ccc(Br)cc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Cc2ccnc3ccc(Br)cc23)n1
Temperature: -70 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
Dissolve 6-bromo-4-methyl-quinoline (38.5 g, 153 mmol) in 600 mL dry THF. Cool to −70° C. and treat with the dropwise addition of 0.5 M potassium hexamethyldisilazane (KN(SiMe3)2 (400 mL, 200 mmol) over 2 hours while keeping the temperature below −65° C. Stir the resultant solution at −70° C. for 1 hour and add a solution of 6-methylpyridine-2-carboxylic acid methyl ester (27.2, 180 mmol) in 100 mL dry THF dropwise over 15 minutes. During the addition, the mixture will turn from dark red to pea-green and form a precipitate. Stir the mixture at −70° C. over 2 hours then allow it to warm to ambient temperature with stirring for 5 hours. Cool the mixture then quench with 12 N HCl to pH=1. Raise the pH to 9 with solid potassium carbonate. Decant the solution from the solids and extract twice with 200 mL ethyl acetate. Combine the organic extracts, wash with water and dry over potassium carbonate. Stir the solids in 200 mL water and 200 mL ethyl acetate and treat with additional potassium carbonate. Separate the organic portion and dry with the previous ethyl acetate extracts. Concentrate the solution in vacuo to a dark oil. Pass the oil through a 300 mL silica plug with methylene chloride then ethyl acetate. Combine the appropriate fractions and concentrate in vacuo to yield an amber oil. Rinse the oil down the sides of the flask with methylene chloride then dilute with hexane while swirling the flask to yield 38.5 g (73.8%) of the desired subtitled intermediate as a yellow solid. MS ES+=341 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[C:19]([O:20][CH3:21])=[CH:18][C:16]([NH2:17])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:17][C:16]2[CH:18]=[C:19]([O:20][CH3:21])[C:13]([O:12][CH3:11])=[CH:14][C:15]=2[N+:22]([O-:24])=[O:23])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Product: COc1cc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])cc1OC

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4,5-dimethoxy-2-nitroaniline as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.84 (s, 1H), 9.04 (d, J=1.8, 1H), 8.66 (s, 1H), 8.25-8.21 (m, 1H), 7.77 (s, 1H), 7.53 (d, J=8.7, 1H), 4.07 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:18]2[N:17]=[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:15]([CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:43]1([CH2:49][CH2:50][CH2:51]Br)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[C:18]2[N:17]=[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:15]([CH2:28][CH2:29][CH2:30][CH:31]3[CH2:32][CH2:33][N:34]([CH2:51][CH2:50][CH2:49][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:35][CH2:36]3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A solution of 4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (177 mg, 0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: P(O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)(O)(O)=O.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].[CH:39]1[CH:44]=[N+:43]([C@@H:45]2[O:49][C@H:48]([CH2:50][O:51][P:52]([O:55][P:56]([O:59][CH2:60][C@H:61]3[O:65][C@@H:64]([N:66]4[C:70]5[N:71]=[CH:72][N:73]=[C:74]([NH2:75])[C:69]=5[N:68]=[CH:67]4)[C@H:63]([O:76][P:77]([OH:80])([OH:79])=[O:78])[C@@H:62]3[OH:81])([OH:58])=[O:57])([OH:54])=[O:53])[C@@H:47]([OH:82])[C@H:46]2[OH:83])[CH:42]=[C:41]([C:84]([NH2:86])=[O:85])[CH:40]=1.[Cl-].[Mg+2].[Cl-].C(OP(O)(O)=O)[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O.P(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(O)(O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH:72]1[N:73]=[C:74]([NH2:75])[C:69]2[N:68]=[CH:67][N:66]([C@@H:64]3[O:65][C@H:61]([CH2:60][O:59][P:56]([O:55][P:52]([O:51][CH2:50][C@H:48]4[O:49][C@@H:45]([N:43]5[CH:42]=[C:41]([C:84]([NH2:86])=[O:85])[CH2:40][CH:39]=[CH:44]5)[C@H:46]([OH:83])[C@@H:47]4[OH:82])([OH:54])=[O:53])([OH:58])=[O:57])[C@@H:62]([OH:81])[C@H:63]3[O:76][P:77]([OH:80])([OH:79])=[O:78])[C:70]=2[N:71]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Agent: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@@H]1O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reaction time: 0.5 h

Procedure:
The concentration of α-glucose 1-phosphate is determined according to the following procedure: 17.1 mg of Na2EDTA is dissolved in 47 mM potassium phosphate buffer (pH 7.0) to prepare 100 ml of a solution. A mixture of 2.5 ml of the solution, 100 μl of a 14.8 mM NADP+ solution, 100 μl of a 26 mM magnesium chloride solution, 100 μl of a 1.34 mM glucose 1,6-diphosphate solution, 50 μl of a 31 unit/ml phosphoglucomutase solution, 50 μl of a 35 unit/ml glucose 6-phosphate dehydrogenase solution, and 100 μl of a sample solution is incubated at 30° C. for 30 min. and subjected to spectrophotometric measurement at 340 nm to give the amount of produced NADPH, thus determining indirectly the amount of α-glucose 1-phosphate in the sample solution.