Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:9][C@H:8]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[Si:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][C@@H:35]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:36]([CH3:39])[CH2:37][CH3:38])=[CH:29][CH:28]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C=O)C.C(OCC)C.ClCCl>[Si:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:34][C@@H:35]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])[C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:10]([C@@H:8]2[CH2:9][C@H:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:12])=[CH:29][CH:28]=1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: CC[C@H](C)[C@@H](CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 35 °C
Yield: 74.6 %

Procedure:
A solution of trans-2-pyridin-2-yl-cyclopropylcarboxylic acid (270 mg, 1.7 mmol) and dichloromethane (15 mL) was treated with oxalyl chloride (170 μL, 2.0 mmol) and DMF (1 drop). The resulting reaction mixture was maintained at 35° C. for 3 h, then concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (15 mL), and treated with tert-butyl (2S,3S)-1-(4-(tert-butyldimethylsilyloxy)phenylamino)-3-methylpentan-2-ylcarbamate (700 mg, 1.7 mmol) and triethylamine (690 μL, 5.0 mmol). The reaction mixture was maintained at room temperature overnight, then diluted with diethyl ether (30 mL) washed with saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL), then dried over MgSO4, filtered and concentrated to afford a residue that was purified by column chromatography on silica gel (eluting with 15% ethyl acetate in hexanes) to afford tert-butyl (2S,3S)-1-(N-(4-(tert-butyldimethylsilyloxy)phenyl)-trans-2-(pyridin-2-yl)cyclopropanecarboxamido)-3-methylpentan-2-ylcarbamate (720 mg, 77% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.04-8.13 (m, 1H), 7.25-7.36 (m, 1H), 6.91-7.00 (m, 1H), 6.87-6.91 (m, 1H), 6.76-6.86 (m, 2H), 6.55-6.62 (m, 1H), 6.46-6.55 (m, 1H), 4.83-4.98 (m, 1H), 4.15-4.27 (m, 1H), 3.45-3.64 (m, 1H), 2.81-2.93 (m, 1H), 2.23-2.48 (m, 1H), 1.68-1.81 (m, 1H), 1.37 (s, 3H), 1.29-1.52 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 1.15-1.22 (m, 1H), 0.86-0.97 (m, 1H), 0.78 (d, J=5.1 Hz, 9H), 0.67-0.71 (m, 3H), 0.60-0.67 (m, 3H), −0.06-0.02 (m, 6H); LRMS (ESI) m/e 568.3 [(M+H)+, calcd for C32H50N3O4Si 568.3].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH3:23])[C:11](=[O:24])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH3:23])[C:11](=[O:24])[CH2:10][N:9]=2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2c1cccc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2c1cccc(-c2ccccc2)c1
Temperature: 115 °C
Yield: 12.9 %

Procedure:
Heat at 115° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.26 mmol) of 5-(3-bromophenyl)-7,8-dimethoxy-1-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one IIax, 38 mg (0.31 mmol) of benzene boronic acid, 63 mg (0.30 mmol) of K3PO4, 9 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) in 1 ml of DMF. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt 1/hexane 1). Recrystallize in EtOH. One obtains 13 mg of the abovenamed powder as colorless crystals. Yield: 13%. M: 127° C. 1H-NMR (CDCl3, 200 MHz): d 3.42 (s, 3H, NCH3), 3.77 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.34 (AB system, ?d=1.00, JAB=10.5, 2H, CH2), 6.78 (s, 1H Ar), 6.80 (s, 1H Ar), 7.39–7.90 (m, 9H Ar).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:33][CH2:34][C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1cccnc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1cccnc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 72.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-(aminomethyl)pyridine (available from Aldrich Chemical Company, Inc.; 67 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(pyridin-3-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (85 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 9.19 (t, J=5.9 Hz, 1H), 8.66 (s, 1H), 8.55 (d, J=3.5 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.90-8.01 (m, 3H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.45-7.55 (m, 3H), 4.57 (d, J=5.8 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([O:18]C)[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:6]=2[CH2:5][CH2:4]1.[BrH:20]>>[BrH:20].[OH:18][C:11]1[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:9][CH2:8][C:7]=2[CH:10]=1
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCN(C)CC2
Agent: Br
Agent: Cl
Product: CN1CCc2cc(O)c(S(C)(=O)=O)cc2CC1

Procedure:
Following the procedure of Example 4, 3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrochloride was reacted with 48% hydrobromic acid to give 8-hydroxy-3-methyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 310° (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:17]#[CH:18])[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])[CH3:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:18]#[C:17][C:5]2[CH:6]=[C:7]3[C:12](=[C:3]([CH2:1][CH3:2])[CH:4]=2)[O:11][C:10]([CH3:13])([CH3:14])[CH2:9][C:8]3([CH3:16])[CH3:15])=[CH:27][CH:28]=1
Reactant: C#Cc1cc(CC)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure F and using 8-ethyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 48, 0.033 g, 0.136 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.034 g, 0.12 mmol), triethyl amine (2 mL), tetrahydrofuran (2 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) the title compound was obtained (0.035 g, 73%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:30])([F:31])[F:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccccc1C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
5.6 g of manganese dioxide were added to a solution of 560 mg (1.3 mmol) of N-[2-t-butyl-5-(hydroxymethyl)phenyl]-3-(2-trifluoromethylphenyl)octanamide (prepared as described in Preparation 19) in 20 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then filtered using a Celite (trade mark) filter aid, and the manganese dioxide used was washed several times with methylene chloride. The filtrate was combined with the washings and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 511 mg (yield 91 %) of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>N1C=CC=CC=1>[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH:22]([NH:25][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=2)[CH2:21][CH2:20]1
Reactant: CC1(C)CCC(N)CC1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)NC2CCC(C)(C)CC2)ccc1OC(C)=O
Yield: 86.9 %

Procedure:
Using 8.9 g of 4-acetoxy-3-methoxycinnamoyl chloride, 3.81 g of 4,4-dimethyl-1-cyclohexylamine, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 8.99 g of N-(4,4-dimethylcyclohexyl)-4-acetoxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1O)([O-])=O.[I-].[Na+].[I-]>>[NH2:14][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:1])[CH:13]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1O
Agent: [I-]
Agent: [Na+]
Product: Nc1cc(N)c2ccccc2c1

Procedure:
In Scheme 1, conversion of 2,4-dinitro-1-hydroxynaphthalene (Martius Yellow; 1) to the iodide (3) is carried out by conversion to the trifluorosulfonate 2, followed by reaction with NaI. Concomitant reduction of the two nitro groups and removal of the iodine from 3 with SnCl2 then gave the 1,3-diaminonaphthalene 4. Protection of the amines with BOC anhydride, followed by electrophilic iodination with NIS (general method of Boger et al., J. Org. Chem., 2001 66, 5163), gave iodide 5. Allylation of the carbamate (NaH/allyl bromide) to give 6, followed by a Bu3SaH promoted 5-exo-trig free-radical cyclization of this with in situ TEMPO (general method of Boger et al.; J. Org. Chem., 2001, 66, 5163) gave 7, which was subsequently reduced (Zn/AcOH) to the alcohol 8 in quantitative yield. The alcohol was converted to the chloride 9 with Ph3P/CCl4. Acid-catalyzed deprotection (TFA) of 9 followed by regioselective coupling with 4-methoxysuccinic acid using EDCI gave the required 10a. This was deblocked by a suitable reagent, (for example, Grubb's carbene [Alcaide et al., Org. Lett., 2001, 3623] or preferably, sodium phenylsulfonate/camphorsulfonic acid/Pd(Ph3P)4 (modification of the method of Honda et al., J. Org. Chem. 1997, 62 8932) to the required 11a. This provides a 10-step synthesis of 11a from 1, with an overall yield of 32%. A similar synthesis gave the analogue 11b in 19% overall yield.
Reaction SMILES: [Se](O)(O)=[O:2].[CH3:5][O:6][C:7](=[O:21])[CH2:8][C:9]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([CH3:20])[CH:13]=[N:14]2>O1CCOCC1.O>[CH3:5][O:6][C:7](=[O:21])[CH2:8][C:9]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([CH:20]=[O:2])[CH:13]=[N:14]2
Reactant: O=[Se](O)O
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1c(Cl)ccc2ncc(C=O)nc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Selenious acid (645 mg, 5.00 mmol, 1.1 equiv) was added to a solution of (6-chloro-3-methyl-quinoxalin-5-yl)-acetic acid methyl ester in dioxane (30 ml). The reaction mixture was heated to 100° C. After 60 minutes, an additional portion of selenious acid (645 mg) was added, and heating was continued for another 60 minutes. After cooling, the reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 80:20) to afford the title compound (966 mg, 81%). MS (ES+): 264 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4=[CH:26][S:27][CH:28]=[C:22]4[NH:21][C:20]3=[O:29])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CN([CH:35]=[O:36])C>>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4=[CH:26][S:27][CH:28]=[C:22]4[N:21]([CH2:22][CH2:23][C:24]([O:36][CH3:35])=[O:25])[C:20]3=[O:29])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=c1[nH]c2cscc2c(=O)n1CCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CN(C)C=O
Product: COC(=O)CCn1c(=O)n(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)c2cscc21
Yield: 80.5 %

Procedure:
The title compound was produced following the procedure of Example 1 using 4.28 g (9.5 mmol) of 3-[4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl]thieno[3,4-d]pyrimidine-2,4-dione in DMF at 45° C. for 16 hours to produce methyl 3-[3-[4-[4(3-trifluoromethylpheny)piperazin-1-yl]butyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate in 80.5% yield (4.1 g).
Reaction SMILES: O.[OH-].[Li+:3].[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:10]([C:17]([O:19]CC)=[O:18])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=1)[CH3:5].C(=O)=O>O.O1CCOCC1>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]([C:17]([O-:19])=[O:18])=[C:11]([C:13]([CH3:15])([OH:16])[CH3:14])[N:12]=1)[CH3:5].[Li+:3]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
A solution of 51.5 mg of lithium hydroxide monohydrate in 8 ml of water was added to a solution of 600 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 86(a)] in 19.5 ml of dioxane, whilst ice-cooling, and the mixture was stirred at 5°-10° C. for 16 hours. At the end of this time, a small piece of dry ice was added, and the reaction solution was concentrated by evaporation under reduced pressure down to approximately 8 ml. The concentrate was then mixed with ethyl acetate and sodium chloride and stirred. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give lithium 2-ethoxymethyl-4-(1-hydroxyl-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as an amorphous powder. The whole of this product was dissolved in 6 ml of N,N-dimethylacetamide, and 113 mg of potassium carbonate were added to the resulting solution, after which a solution of 240 mg of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity grade: 74%) in 2 ml of N,N-dimethylacetamide was added dropwise to the mixture. The mixture was then stirred at 50° C. for 1 hour, after which it was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 548 mg of the title compound as crystals, melting at 129°-130.5° C.
Reaction SMILES: [I-].[C:2]1([S+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH3:32])[CH:26]=[CH:25][C:24]([S:27]([O:30]C)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(#N)C>[C:21]1([CH3:32])[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [I-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Acetonitrile (500 ml) was added to triphenylsulfonium iodide (390.3 g; 1.0 mol) and methyl p-toluenesulfonate (223.5 g; 1.2 mol). The resultant mixture was heated at 82° C.-85° C. and refluxed for 5 hours while being stirred. The reaction mixture was cooled, and acetonitrile was removed through distillation under reduced pressure. The thus-obtained pale-yellow solid was washed with methylene chloride, and dried under vacuum, to thereby yield 369.4 g of triphenylsulfonium p-toluenesulfonate (yield: 85%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.Cl.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[NH4+]>CO>[CH2:15]([O:22][N:23]=[C:10]1[CH2:11][CH2:12][N:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1nnc(N2CCC(=NOCc3ccccc3)CC2)o1
Yield: 96.6 %

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-one (1.52 g, 8.39 mmol), O-benzylhydroxylamine hydrochloride (1.50 g, 9.23 mmol) and ammonium acetate (1.62 g, 21.0 mmol) in MeOH (34.5 mL) was heated to reflux for 2 hours under nitrogen. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient from AcOEt to AcOEt/EtOH 9:1 (v/v) as eluent to yield the title compound as a light yellow viscous oil (2.32 g, 96%).
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.C1(C)C=CC(S([Cl:19])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:19][CH2:8][C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1
Reactant: Cc1cc[n+]([O-])c(C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccnc(CCl)c1
Yield: 364.4 %

Procedure:
2,4-Lutidine-1-oxide (10 g, 8.10 mmol) was dissolved in anhydrous dioxane (125 ml) under nitrogen atomsphere, and herein p-toluenesulfonyl chloride (31.5 g, 162 mmol) was added and refluxed for 5 hours. The solution was neutralized with the saturated aqueous solution of potassium carbonate and extracted twice with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to get crude product. The residue was separated and purified by column-chromatography over silica gel to obtain 2-chloromethyl-4-methylpyridine (4.18 g, yield=36%).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](Br)[CH3:20].[OH-].[K+].Cl.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(O)C.O.ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:14]=1[CH:19]([CH3:20])[CH2:2][C:3]2=[O:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Br)c1ccccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1CC(=O)c2cccc(Br)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium ethoxide in ethanol obtained from 15.4 g (0.67 mmol) of sodium and 360 ml of anhydrous ethanol, a solution of 215 g (1.34 mmol) of diethyl malonate in 240 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 137 g (0.52 mmol) of 1-bromo-2-(1-bromoethyl)benzene in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 105 g of potassium hydroxide in 280 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×200 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 130 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 160 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 80.0 g (0.60 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 500 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×300 ml of methyl-tert-butyl ether. The combined organic extract was dried over K2CO3 and then evaporated to dryness. The title product was isolated fractional distillation in vacuum, bp 108-112° C./3 mm Hg. Yield 101 g (86%).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CCCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 69.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.