Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:19][C:20]4[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=4)=[C:13]([C:15]([O:17]C)=O)[N:14]=[C:7]3[C:6]=2[CH:26]=1.C[O-].[Na+].C([NH2:33])=O>>[Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:19][C:20]4[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=4)=[C:13]([C:15]([NH2:33])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 11 mg (11% crude yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([N:8]2[N:12]=[N:11][C:10]([CH:13](OS(C)(=O)=O)[CH3:14])=[N:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH3:28]>C(#N)C>[CH2:27]([O:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([CH:13]([C:10]2[N:11]=[N:12][N:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:20])[N:9]=2)[CH3:14])[CH2:36][CH2:37]1)=[O:31])[CH3:28]
Reactant: CC(OS(C)(=O)=O)c1nnn(-c2cc(Cl)ccc2F)n1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(C)c2nnn(-c3cc(Cl)ccc3F)n2)CC1
Yield: 73.1 %

Procedure:
The title compound (25.2 mg, 72%, yellow oil, ˜90% pure) was prepared from methanesulfonic acid 1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester (˜29.5 mg, 0.09 mmol) using potassium carbonate (38 mg, 0.27 mmol) and 1-ethoxycarbonyl piperazine (20 uL, 0.14 mmol) in acetonitrile (1.5 mL) at 80° C. overnight. The product was purified by chromatography using a silica SPE tube (25-35% ethyl acetate in hexane). 1H NMR (CDCl3) δ (ppm): 7.91 (dd, 1H), 7.51 (ddd, 1H), 7.33 (t, 1H), 4.32 (q, 1H), 4.11 (q, 2H), 3.52 (m, 4H), 2.61 (m, 2H), 2.51 (m, 2H), 1.65 (d, 3H), 1.24 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(Oc2ccccc2)cc1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (6.49 g, 30.9 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.23 g, 30.9 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 1-(chloromethyl)-4-(phenyloxy)benzene (8.1 g, 37.0 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was heated under reflux overnight. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(phenyloxy)phenyl)methyl)propionate (7.76 g, crude, 64%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:64][CH:65]([CH3:68])[CH2:66][NH2:67]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:13]=1)[C:8]([NH:67][CH2:66][CH:65]([CH3:68])[CH3:64])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)NCC(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
A mixture of compound 13b (90 mg, 0.21 mmol), DIPEA (134 mg, 1.04 mmol) and HATU (157 mg, 0.41 mmol) in DMF was stirred at rt for 1 h, then 2-methylpropan-1-amine (18 mg, 0.25 mmol) was added. The mixture was stirred at rt overnight and concentrated. The product was isolated by CC to get compound 13 (45 mg, 45%). 1H-NMR (400 MHz, DMSO-d6) δ: 8.57 (m, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 6.94 (s, 2H), 6.39 (s, 1H), 3.82 (d, J=5.6 Hz, 2H), 3.09 (s, 2H), 2.45 (s, 3H), 1.85-1.84 (m, 1H), 1.46 (s, 3H), 1.33-1.25 (m, 12H), 0.94-0.88 (m, 9H), 0.66-0.63 (m, 2H). MS Found: 488 (M+1).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[CH2:7]([C:9]1[N:10]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20](OCCC)=[N:21][CH:22]=[C:23]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:24]=3)=[N:14][C:13]=12)[CH3:8]>CC(O)C>[CH2:7]([C:9]1[N:10]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[N:21][CH:22]=[C:23]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:26])=[O:27])[CH:24]=3)=[N:14][C:13]=12)[CH3:8]
Reactant: CCCOc1ncc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)cnc3OC(C)C)[nH]c(=O)c2nn1Cc1ccccn1

Procedure:
Potassium t-butoxide (290 mg, 2.60 mmol) was added to a stirred solution of the title compound of Example 20 (239 mg, 0.43 mmol) in propan-2-ol (7 ml) under nitrogen and the reaction mixture heated under reflux for 48 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (20 ml) and ethyl acetate (20 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:48]2[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 6-Chloro-nicotinic acid (3.00 g, 19.0 mmol) in 30 mL dimethylformamide was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (10.9 g, 20.9 mmol), 1-methylpiperazine (2.30 g, 22.1 mmol). and triethylamine (2.18 g, 21.5 mmol). After stirring for 18 hours, this was partitioned between ethyl acetate and water. The ethylacetate layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (elution with 3% methanol/dichloromethane) to yield (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.50 g, 9.33 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][N:27]=[N+:28]=[N-:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
In a flask protected by a safety screen, a solution of N-t-butoxycarbonyl-4(S)-t-butyldimethylsilyloxy-2(S)-methane-sulfonyloxy methyl pyrrolidine(10.40 g, 25.39 mmol) and tetrabutyl-ammonium azide (8.18 g, 28.7 mmol) in toluene (250 mmol was stirred at 80° C. for 5 hr. The reaction was cooled to room temperature and diluted with EtOAc (250 mn), washed with water and brine and dried (Na2SO4). The solvent was evaporated in vacuo to afford the title compound as a yellow oil which was used in the next step without furthur purification.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].CO[Na].[C:13](OC)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:1][CH:2]1[O:9][C:24]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CC(O)CNCC(C)O
Reactant: CCCCCCCCCCCC(=O)OC
Agent: CC(=O)[O-]
Agent: CO[Na]
Agent: [Zn+2]
Product: CCCCCCCCCCCC12OC(C)CN1CC(C)O2
Temperature: 75 °C

Procedure:
In a first stage to a reactor, equipped with a distillation column, condenser, and graduated receiver, 199.8 g (1.5 mol) of diisopropanol amine (DIPA) and 7.5 g of CH3ONa (30% in methanol) were added and the batch heated to 75° C. 160.5 g (0.75 mol) of methyl laurate were added during 2 hours at 75° C. Temperature was gradually increased during 3 hours. Methanol has been removed at lower pressure 26,660 Pa) and at 120° C. and excess of DIPA has been removed at a pressure below 133 Pa and at 140° C. The so prepared amide looked as yellow fat (melting temperature of above 130° C). In a second stage 0.5 weight % of zinc acetate, based on the intermediate product after stage 1 were added and the batch was heated at 180° C. for 6 hours. Fraction distillation has been done at a pressure below 133 Pa. Three fractions were obtained: I) with boiling point <105° C.; amount above 5 weight %; mainly DIPA; II) with boiling point 105-145° C.; amount 50 weight %; amide acetal (purity 90%) and III) 45 weight %—distillation rest. The yield of amide acetal calculated on methyl laurate was 43%. Initial color and color stability during storage (on shelf) of an amide acetal prepared according to the invention and a comparative amide acetal prepared from nitriles have been evaluated. The amide acetal according to the invention shows a better initial color and better color stability than the amide acetal prepared from nitrites.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([CH3:36])([CH3:35])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[N:25][N:26]=2)[CH:16]=3)=[C:8]([CH3:34])[CH:7]=1.[OH-].[Na+].C1COCC1.Cl>CO.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[O:23][C:22]([C:17]3[CH:16]=[C:15]4[C:20]([CH:21]=[C:13]([C:9]5[C:8]([CH3:34])=[CH:7][C:6]([CH2:5][C:4]([CH3:35])([CH3:36])[C:3]([OH:37])=[O:2])=[CH:11][C:10]=5[CH3:12])[NH:14]4)=[CH:19][CH:18]=3)=[N:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1cc2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[nH]1
Temperature: 50 °C

Procedure:
Suspend 3-(4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-indol-2-yl}-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (262 mg, 0.510 mmol) in MeOH (2.6 mL)/1 N NaOH (2.6 mL) and heat to 50° C. for 3 h. Add THF (2.6 mL) and heat to 50° C. for 15 h. Add 1 N NaOH (2.6 mL), THF (2.6 mL), and NaOH (225 mg, 5.63 mmol) in water (1 mL). Heat the reaction at 50° C. until the ester is not observed by LC/MS. Concentrate the reaction under reduced pressure. Adjust the pH to 2 with 1 N HCl. Collect the resulting precipitate by filtration and rinse the solid with Et2O to afford a light yellow solid: (M+H)+ 500.2.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>C(O)C.[Pd]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCOc1ccc(N)cc1

Procedure:
4-(3-(dimethylamino)propoxy)nitrobenzene (4.4 g, 19.6 mmol) was hydrogenated over Pd (10% on C, 0.4 g) in ethanol (50 ml) for 16 h. The catalyst was filtered off and the solvent removed under reduced pressure to afford the title compound as a brown oil. MS (m/z)=195.3 (M+H+); Calc'd for C11H18N2O=194.28.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-:34])=[CH:17][C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
19.47 g (57.19 mmol) of 1-[4-(tert-Butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline was dissolved in 500 ml of methylene chloride and 15.51 g (62.91 mmol) of 70% m-chloroperbenzoic acid was added thereto. The resulting mixture was stirred overnight at room temperature. A sodium hydrogencarbonate aqueous solution was added to the reaction mixture and the reaction mixture was extracted twice with chloroform. The organic phase was washed with brine and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was purified by aluminum column chromatography (chloroform:methanol=50:1 to 10:1 (v/v)). Finally, the resulting product was triturated with diethyl ether and collected by filtration to obtain 15.88 g (44.55 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline-5-oxide shown below as yellowish white powder. ##STR54## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3280, 2970, 1710, 1540, 1365, 1250, 1170, 1140, 850, 760, 630.
Reaction SMILES: [Li].C1COCC1.C([O:14][CH2:15][C@@H:16]([CH3:33])[CH2:17]/[CH:18]=[CH:19]/[C@H:20]([CH3:32])[C@@H:21]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:22][CH3:23])C1C=CC=CC=1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:33][C@@H:16]([CH2:17]/[CH:18]=[CH:19]/[C@H:20]([CH3:32])[C@@H:21]([O:24][Si:25]([CH2:28][CH3:29])([CH2:30][CH3:31])[CH2:26][CH3:27])[CH2:22][CH3:23])[CH2:15][OH:14]
Reactant: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)/C=C/C[C@H](C)COCc1ccccc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)/C=C/C[C@H](C)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
Lithium (39.4 mg, 5.62 mmol) was added to a THF (25 ml) solution of di-tert-butyldiphenyl (1.87 g, 7.02 mmol) while ice cooling and the reaction solution was stirred at room temperature for three hours. The reaction solution turned dark green during stirring. This solution was added dropwise to THF (5 ml) solution of {[(1S,2S,3E,6S)-7-benzyloxy-1-ethyl-2,6-dimethylhept-3-en-1-yl]oxy}(triethyl)silane (500 mg, 1.28 mmol) slowly (at such a rate that green of the reaction solution was maintained) cooled to −78° C. under stirring. After the reaction solution was stirred at the same temperature for three hours, a saturated ammonium chloride aqueous solution was added thereto and the mixture was warmed to room temperature. After the reaction solution was diluted with ethyl acetate, it was washed with brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=15:1) to obtain the title compound (296 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:29])([F:28])[F:27].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:27])([F:29])[F:28]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cc(Cl)cc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2,4,6-trichloroaniline (3.9 g.) was dissolved in dimethylformamide (20 ml.) and carefully added to sodium hydride (obtained by washing sodium hydride in mineral oil (2.0 g; 50%) with petrol) suspended in dimethylformamide (10 ml.) at 10° C. When the addition was complete the temperature of the mixture was allowed to rise to the ambient temperature over a period of 30 minutes, before being cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (5.4 g.) in dimethylformamide (20 ml.) was slowly added, and the mixture stirred at the ambient temperature for 5 hours, and allowed to stand for further 16 hours. The mixture was poured into iced water and the resultant mixture acidified with concentrated hydrochloric acid. The precipitate was collected by decanting off the supernatant liquid and recrystallised from methylated spirit to yield 2(2,4,6-trichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 105° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7](O)(=[O:10])[CH2:8][CH3:9].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:35])[C:19]2[O:25][C:24]3[C:26]([Cl:31])=[CH:27][C:28]([NH2:30])=[CH:29][C:23]=3[CH2:22][S:21](=[O:33])(=[O:32])[C:20]=2[CH:34]=1)=[O:15]>ClCCl.CN(C=O)C>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:35])[C:19]2[O:25][C:24]3[C:26]([Cl:31])=[CH:27][C:28]([NH:30][C:7](=[O:10])[CH2:8][CH3:9])=[CH:29][C:23]=3[CH2:22][S:21](=[O:33])(=[O:32])[C:20]=2[CH:34]=1)=[O:15]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Reactant: CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)Nc1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Reaction time: 18 h

Procedure:
A solution of oxalyl chloride (0.17 mL, 2.03 mmol) and propionic acid (0.15 mL, 2.03 mmol) in dichloromethane (20 mL) was stirred for 1 h. Compound of Example 1 (0.5 g, 1.35 mmol) in DMF (5 mL) was added to the reaction mixture at 25° C. and stirred for 18 h. The solvent was removed under vacuum, water (25 mL) was added and the solid precipitated was filtered. The crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.28 g, (60%); mp: 226-228° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.06 (t, 3H, CH3), 2.33 (q, 2H, CH2), 2.64 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 5.30 (s, 2H, CH2), 7.66 (d, 1H, Ar), 7.88 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 10.26 (s, 1H, NH); MS: m/e (EI) 423 (M+); analysis: C19H18ClNO6S requires C, 53.66; H, 4.28; N, 3.30; Cl, 8.32; S, 7.56. found: C, 53.38; H, 4.27; N, 3.48; Cl, 8.64; S, 7.75%.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:10]2[CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:19][CH2:18]1)=[O:36])[CH3:39]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 68.7 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14 mmol) and ethyl choroformate (0.186 g, 1.71 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): 81.21 (311, t), 1.42 (4H, m), 1.81 (3H, d), 2.92 (2H, m), 4.12 (2H, m), 7.26 (5H, d), 7.52 (2H, d), 7.92 (4H, d), 8.41 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C:7]([NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:22]([C:3]1[C:2]([NH:1][S:24](=[O:27])(=[O:26])[NH2:25])=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]([NH:10][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:8])#[N:23]
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)c1ccncc1
Reactant: NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(COc1cccc(NS(N)(=O)=O)c1C#N)NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)isonicotinamide (10.76 g, 34.67 mmol) in DMA (35 mL) was added sulfamoyl chloride (7.98 g, 69.34 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The resulting solution was poured into 200 mL of ice cooled NaHCO3 aqueous and stirred for 30 minutes, the precipitate was collected by filtration, after dry obtained 12.2 g of clean product as an off white solid in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 6H), 4.32 (s, 2H), 6.93 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (s, 2H), 7.53 (t, J=8.8 Hz, 1H), 7.67 (d, J=6 Hz, 2H), 8.29 (s, 1H), 8.66 (d, J=6.4 Hz, 2H), 9.45 (s, 1H). MS 390 (MH+).
Reaction SMILES: [CH2:1]1COCC1.[CH2:6]([CH:13]([NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[C:14](=[O:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Mg]Cl.O>C(OCC)(=O)C>[CH2:6]([CH:13]([NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[C:14]([OH:16])([CH3:1])[CH3:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)=O)ccc1-n1cnc(C)c1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)(C)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (1.0 mL) solution of (E)-N-(1-benzyl-2-oxopropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (12.0 mg), methyl magnesium chloride (3MTHF solution, 198 μL) was added at −78° C., the reaction solution was allowed to be warmed to room temperature and agitated for further 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate→ethyl acetate ethanol=10:1), and 6.8 mg of the title compound was obtained. The physical properties of the compound are as follows.