Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][C:27]1([CH3:36])[CH2:32][C:31](=[O:33])[CH2:30][C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:31]3([OH:33])[CH2:30][C:29]([CH3:34])([CH3:35])[O:28][C:27]([CH3:36])([CH3:26])[CH2:32]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CC(C)(C)OC(C)(C)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 2,2,6,6-tetramethyl tetrahydropyran-4-one (WO 2005012220). 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.4 Hz), 7.98 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.34 (d, 1H, J=2.0 Hz), 5.74 (br s, 1H), 2.32 (m, 2H), 2.08 (m, 2H), 1.87 (m, 4H), 1.56-1.58 (m, 8H), 1.56 (s, 6H), 1.21 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:4]=2[C:3]=1[F:24].[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C>[CH:25]1([S:28]([N:12]2[C:5]3[C:6]4[O:10][C:9]([CH3:11])=[N:8][C:7]=4[C:2]([F:1])=[C:3]([F:24])[C:4]=3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:13]2=[O:23])(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(I)cc3F)c2o1
Agent: CN(C)c1ccncc1
Product: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Yield: 56.3 %

Procedure:
Intermediate I-22a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-18a: 80 mg, 0.178 mmol), cyclopropanesulfonyl chloride (37.75 mg, 0.269 mmol), TEA (54.46 mg, 0.534 mmol) and DMAP (10 mg) using procedures analogous to those described above for Intermediate I-19a to afford 55 mg of the product (56.3% yield). H1NMR (CDCl3, 300 MHz): δ 7.72-7.64 (m, 2H), 7.30-7.22 (m, 1H), 3.34-3.24 (m, 1H), 2.74 (s, 3H), 1.74-1.60 (m, 2H), 1.34-1.20 (m, 2H). LCMS: 81.9%; 549.9 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.[Cl-].[NH4+].[O:29]1CCC[CH2:30]1>>[F:19][C:20]1[CH:25]=[C:24]([CH2:26][CH2:30][OH:29])[CH:23]=[CH:22][N:21]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: OCCc1ccnc(F)c1
Temperature: -80 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of anhydrous diisopropylamine (18.5 mL, 0.13 mol) in anhydrous tetrahydrofuran (160 mL) was added dropwise at −80° C., under argon, a 1.3 M n-butyllithium solution in hexane (100 mL, 0.13 mol). The mixture was stirred at −80° C. for 1 h before addition dropwise of a solution of 2-fluoro-4-picoline (41) (9.00 g, 6.30 mmol) in anhydrous tetrahydrofuran (60 mL). The mixture was stirred at −80° C. for 1 h once again before addition dropwise of a p-formaldehyde (16.6 g, 0.55 mol) suspension in anhydrous tetrahydrofuran (100 mL). The mixture was stirred at −80° C. for 1 h and then at room temperature for 12 h. A saturated aqueous ammonium chloride solution (450 mL) was added to the mixture. The solution was decanted and the aqueous layer was extracted with dichloromethane (4×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue obtained was chromatographed (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 42 (7.25 g, 51.4 mmol) as an orange-coloured oil. Yield 57%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.32; IR (CCl4) ν 1046, 1149, 1278, 1413, 1613, 2800-3000, 3100-3600, 3634 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.87 (t, 2H, J=6.3 Hz), 3.87 (t, 2H, J=6.3 Hz), 6.82 (s, 1H), 7.07 (d, 1H, J=5.2 Hz), 8.01 (d, 1H, J=5.2 Hz); MS m/z 141 (M+, 23), 111 (100), 91 (34), 83 (14), 64 (10), 57 (12).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].OC(C(F)(F)F)=O.[CH:34]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][C:40]2=[O:45])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:42]4[CH2:43][CH2:44][N:39]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:40](=[O:45])[CH2:41]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1C1CCCC1
Agent: [F-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C4CCCC4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-cyclopentylpiperazin-2-one TFA salt (129 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 5 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.1 min (conditions 4), MH+=477)
Reaction SMILES: COC(C1ON=C(OC[C:12]2[C:13]([CH2:18]CCC)=[N:14]OC=2C)C=1)=O.CO[C:24]([C:26]1[O:30][N:29]=[C:28]([O:31][CH2:32][C:33]2[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=CN=3)=[N:35][O:36][C:37]=2[CH3:38])[CH:27]=1)=[O:25].[CH2:45]([CH2:47][NH2:48])[OH:46]>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[OH:46][CH2:45][CH2:47][NH:48][C:24]([C:26]1[O:30][N:29]=[C:28]([O:31][CH2:32][C:33]2[C:34]([CH2:39][CH2:44][CH2:43][CH3:42])=[N:35][O:36][C:37]=2[CH3:38])[CH:27]=1)=[O:25]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Product: CC(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NCCO)on1
Yield: 47 %

Procedure:
As described for example 14e, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (201 mg, 0.68 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using ethanolamine (50 mg, 0.82 mmol), instead of isopropyl amine, to the title compound (103 mg, 47%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=1:1 to 0:1). MS: m/e=324.3 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9].[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>CO.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>[Cl:12][CH2:13][C:14]([NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: C=C(C)C(=O)NCCCN
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCNC(=O)CCl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
In a 3-liter 4-neck flask fitted with condenser, stirrer, and 2-dropping funnels were placed N-(3-aminopropyl)methacrylamide hydrochloride (157 g 0.88 moles) in methanol (1.2 L) and 2,6-di-tert-butyl-p-cresol (1.0 g). In one funnel was placed chloroacetyl chloride (100 g, 0.89 mole), and in funnel two was placed triethylamine (178 g, 1.76 mole). The solution was cooled to 0°-5° C. (ice-methanol), and triethylamine was added in a slow stream over 30 minutes, and the chloroacetyl chloride was added over 1 hour. After the addition, the temperature was maintained at 0° C. for 2 hours, the ice bath was removed, and stirring was continued at room temperature overnight. The solvent was removed, and to the residue was added hot ethyl acetate (500 mL). The mixture was filtered to remove triethylamine hydrochloride, then the solid was washed with hot ethyl acetate (500 mL), filtered again, the filtrate combined, and the solvent was removed on a rotary evaporator. The residue was crystallized from ethyl acetate (400 mL) by heating to dissolve, filtering to remove any solid present, and cooling to 0° C. to crystallize. The crude monomer was purified by chromatography on a silica gel packed column. The product was eluted from the column using a 1:1 mixture of ethyl acetate and dichloromethane (4 L). The collected solvent was evaporated, and the residue crystallized from ethyl acetate (300 mL) with 2,6-ditert-butyl-p-cresol (500 mg) to give a white crystalline compound, mp 85°-90° C., 83 g (43% yield). Analysis Calculated C9H15ClN2O2 : C, 49.4; H, 6.9; N, 12.8; Cl, 16.2. Found: C, 49.0; H, 7.6; N, 13.2; Cl, 17.3.
Reaction SMILES: [Cl:1][C:2]1[C:3](NN)=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(O)(=O)C>S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: NNc1nc(F)c(F)cc1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(Cl)cnc1F
Yield: 86.5 %

Procedure:
17.9 g of the compound obtained in Step 2 was added to a mixture of 360 ml of acetic acid and 135 ml of water, and 450 ml of 10% aqueous copper sulfate was added dropwise thereto. The resulting mixture was refluxed for 24 hours while removing water using a Dean-Stark trap, to obtain 12.9 g of the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][OH:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].[CH:37]([Si:40](Cl)([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([CH2:35][O:36][Si:40]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:37]([CH3:39])[CH3:38])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:27])[CH3:28])[CH:20]([CH3:21])[CH3:22])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxamide (9.30 g, 17.9 mmol) synthesized in Example (125d) was dissolved in methylene chloride (180 mL), and triisopropylsilyl chloride (4.25 mL, 19.9 mmol), triethylamine (7.45 mL, 53.5 mmol) and 4-dimethylaminopyridine (2.20 g, 18.0 mmol) were added, followed by stirring at room temperature for 2.5 hours under nitrogen atmosphere. Water (300 mL) was added to separate the solution, and the organic layer was washed with saturated brine and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-35%) to afford the desired compound (10.56 g, yield 87%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:4][CH2:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH3:21])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][N:4]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:3]1
Reactant: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccccc21

Procedure:
As described in Example 2, the title compound was prepared from ethyl 1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride. 1H-NMR (DMSO-d6): δ 10.82 (1H, s), 7.76 (1H, d), 7.65 (1H, s), 7.61 (2H, dd), 7.54 (1H, d), 7.35 (2H, app t), 7.09 (1 H, app t), 6.98 (1 H, app t), 4.22 (2H, q), 3.97 (2H, brs), 1.52 (6H, s), 1.17 (3H, t); MS(ESI): 407 (MH+).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO[C:13]1N=[C:17]([CH:19]=O)[CH:16]=[CH:15][CH:14]=1.O([CH3:23])[Na]>C1COCC1>[C:13]1([CH:23]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:19]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CO)c1ccccc1
Reactant: COc1cccc(C=O)n1
Reactant: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 30 %

Procedure:
2.35 g (17.3 mmol) of 2-hydroxyacetophenone, 2.13 g of 6-methoxy-2-pyridinecarboxaldehyde (15.5 mmol), and 8 ml of 25% NaOCH3 were reacted in 70 ml dry THF to give 1.2 g (30%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.15 (s, 1H), 8.24 (d, J=14.7 Hz, 1H), 8.01 (d, d, J=1.2, 7.8 Hz, 1H), 7.79 (d, J=15.0 Hz, 1H), 7.65 (d, d, J=7.2, 7.2 Hz, 1H), 7.53 (d, d, J=7.2, 7.2 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.06 (d, d, J=0.9, 8.1 Hz, 1H), 6.99 (d, d, J=7.2, 8.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][Si:7]([C:10]#[C:11][C:12]([CH2:14][CH2:15][CH2:16][CH3:17])=[O:13])([CH3:9])[CH3:8]>CCOCC>[CH3:9][Si:7]([C:10]#[C:11][C:12]([OH:13])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][C:3]#[CH:2])([CH3:8])[CH3:6]
Reactant: C#CCBr
Reactant: CCCCC(=O)C#C[Si](C)(C)C
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 grams of magnesium and 10 mg of mercuric chloride in 12 ml of ether is added 0.4 ml of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The stirred mixture is cooled in an ice-water bath and a solution of 9.64 grams of n-butyl trimethylsilylethynyl ketone and 3.51 ml of propargyl bromide in 13 ml of ether added dropwise so that the mixture is very gently boiling during a period of about 40 minutes. After addition is complete, the cooling bath is removed and the mixture is stirred at room temperature for about 1.5 hours. The mixture is recooled in an ice bath and 10 ml of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquor is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving 10.5 grams of a red liquid. The liquid is Kugelrohr-distilled at 60° C./0.25-0.3 mm. The pale yellow liquid distillate which is the desired product weighed 8.5 grams.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[N-].Cl[O:16][C:17]([CH3:20])(C)C.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][CH:3]([O:16][CH2:17][CH3:20])[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[CH3:22]
Reactant: COc1cccc(CC(=O)C=[N+]=[N-])c1
Reactant: CC(C)(C)OCl
Reactant: CCO
Product: CCOC(OCC)C(=O)Cc1cccc(OC)c1
Temperature: -18 °C

Procedure:
Under an argon atmosphere, 1-diazo-3-(3-methoxyphenyl)propan-2-one (82) (501 mg, 2.63 mmol) was dissolved in anhydrous ethanol (5 mL) and cooled to −18° C. To this was added tert-butyl hypochlorite (300 μL, 2.65 mmol) and stirred for an hour at the same temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=10/1) to give 1,1-diethoxy-3-(3-methoxyphenyl)propan-2-one (83) as a pale yellow oily substance (371 mg, 1.47 mmol, 55.8%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg]I.[Mg].CI.Cl>CCOCC>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[CH:5]=1)([CH3:17])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccccc2)c(C)c1
Reactant: C[Mg]I
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: Cc1cc(C(C)(C)O)ccc1-c1ccccc1

Procedure:
A solution of 4-acetyl-2-methylbiphenyl (12.8g, 0.061 mole) in dry ether (340me) was added over 30 minutes to methyl magnesium iodide, (from magnesium, 1.8g, methyl iodide, 5.1ml, and ether 61 ml). The mixture was stirred under reflux for 5 hours, stirred overnight at room temperature and finally decomposed by the dropwise addition of hydrochloric acid (2N; 170ml). The product was isolated in ether washed with aqueous sodium thiosulphate and water, dried, evaporated, and distilled. The product solidified on standing and was recrystallized from light petroleum (b.p. 40°-60° C) to give 4-(1-hydroxy-1-methylethyl)-2-methylbiphenyl, m.p. 60°-64° C. A solution of this (5g) in ethyl acetate (50ml) containing concentrated sulphuric acid (3 drops) was hydrogenated over palladium-charcoal (10%, 0.5g) for 8 hours. The mixture was filtered and the filtrate was concentrated by evaporation. The residue was dissolved in ether (50ml), washed with aqueous sodium hydrogen carbonate, dried, evaporated and distilled to give 4-isopropyl-2-methylbiphenyl, b.p. 93°-94° C/0.3mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[S:22](=[O:25])(=[O:24])[NH2:23])(=[O:11])=[O:10].[CH2:26](O)[CH3:27]>S(Cl)(Cl)=O>[CH2:26]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[C:14]([S:22](=[O:24])(=[O:25])[NH2:23])[CH:15]=1)[CH3:27]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-(2,3-dichloro-benzenesulfonylamino)-3-sulfamoyl-benzoic acid (1.3 g, 3.05 mmol) in ethanol (20 mL) was stirred at RT and a few drops of thionyl chloride were added. The reaction mixture was heated at reflux for 7 h, cooled to RT and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate/hexane (1:1) as eluent to afford the title compound (1.4 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[O:16]=[S:17]1(=[O:40])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=3)=[C:26]([CH3:39])[CH:25]=2)[CH2:19][CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:16]=[S:17]1(=[O:40])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:1][C:2]4[CH:15]=[CH:14][C:5]5[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=5[CH:3]=4)[CH:32]=3)=[C:26]([CH3:39])[CH:25]=2)[CH2:19][CH2:18]1
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCS(=O)(=O)CC5)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][OH:20])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)CC)(C)C.[CH3:31][O:32][C:33]1(OC)[CH:52]=[CH:51][C:36]([C:37](Cl)([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)=[CH:35][CH2:34]1.[O:55]1CCC[CH2:56]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][O:20][C:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:39]=[CH:40][C:41]([O:55][CH3:56])=[CH:42][CH:43]=1)[C:36]1[CH:51]=[CH:52][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COC1(OC)C=CC(C(Cl)(c2ccccc2)c2ccccc2)=CC1
Reactant: O=C(NCCCCCC(O)CCO)OCc1ccccc1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COc1ccc(C(OCCC(O)CCCCCNC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h

Procedure:
8-(N-Cbz-amino)-1,3-octanediol (4, 25 g, 85 mmoles ) was dissolved in anhydrous pyridine (200 mL), evaporated in vacuo and redissolved in anhydrous pyridine (200 mL). Diisopropylethylamine (38.1 mL, 88 mmoles) and 4-dimethylaminopyridine (170 mg) were added. The mixture was stirred under nitrogen and cooled in an ice bath while adding 4,4-dimethoxytrityl chloride (30 g, 88 mmoles) in tetrahydrofuran (200 mL) dropwise over 1.5 hours. Stirring was continued for 15 minutes after the addition was complete. The mixture was evaporated in vacuo and purified by column chromatography on silica gel, eluting with 20:80:1 ethyl acetate:cyclohexane:triethylamine, then 50:50:1 ethyl acetate:cyclohexane:triethylamine and finally, 100:1 ethyl acetate:triethylamine. Evaporation of the appropriate fractions gave 8-(N-Cbz-amino)-3-hydroxy-1-(4,4'-dimethoxytrityloxy)octane (44 g) as a crisp foam. Mass Spectrum: (M+K)+ @m/z 636. 8-(N-Cbz-amino)-3-hydroxy-1-(4,4'-dimethoxytrityloxy)octane (28.4 g, 47.6 mmoles) was dissolved in methanol (200 mL) and hydrogenated over 10% palladium on carbon (2.84 g) @45 psi hydrogen for 2.5 hours. After filtration and evaporation in vacuo there remained 8-(N-Cbz-amino)-1,3-octanediol (21.5 g). Mass Spectrum: (M+K)+ @m/z 502.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH-:9].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CCOCC>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN(C)[C@@H]1CCCC[C@H]1[NH-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 47 %

Procedure:
This titled amide was prepared by general procedure B from trans-2-(dimethylamino)cyclohexylamide and 3-trifluoromethylbenzoyl chloride. The crude oil was converted to the salt with 1 mole of p-toluenesulfonic acid in ether, and was crystallized from MeOH-ether, 47% yield, colorless plates, m.p. 208°-209°. uv λmax 222 nm (ε 22,150); sh 227 (17,900); sh 259 (1,550); sh 266 (1,100); sh 274 (566). ir NH/N+H 3280, 3040; C=O 1660; C=C/amide II 1615, 1595, 1550, 1495; CF3 /SO3 /CN 1335, 1320, 1275, 1200,1180, 1160, 1120, 1075, 1035, 1010; aromatic/SO3- 705, 690, 680. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 314.