Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:35])[CH3:34]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (933 mg, 2.46 mmol) obtained in Example 37 in dichloromethane (20 mL) was added aluminum chloride (721 mg, 5.40 mmol) at −70° C. under an argon atmosphere and the mixture was stirred for 20 minutes. To the reaction solution was added dropwise acetyl chloride (424 mg, 5.40 mmol) at the same temperature and the reaction mixture was gradually warmed to 10° C. The reaction solution was added to ice, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 2:1) to synthesize 873 mg (yield: 84%) of the title compound. Melting point: 176-177° C. (ethyl acetate-hexane). [α]D20=+6.2° (c=0.53, chloroform).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH2:32]([N:34](CC)CC)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][NH:17][C:4]2[N:3]=[C:2]([C:32]#[N:34])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Solvent: CN(C)C=O
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 40.8 %

Procedure:
A solution of 2-chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 9) (1.0 g. 2.31 mmol), zinc cyanide (0.162 g, 1.38 mmol), triethylamine (0.28 g, 2.77 mmol), tetrakis(triphenylphosphine palladium(0) (0.133 g, 0.12 mmol) and N,N-dimethylformamide (3 ml) was heated under a nitrogen atmosphere at 100° C. for 6 hours. The reaction mixture was allowed to cool and partitioned between ethyl acetate (100 ml) and 2 M aqueous sodium hydroxide solution (100 ml). The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting 1:1 mixture of 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile and 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (e.g. see Preparation 15) was separated by column chromatography on silica gel eluting with a gradient system of ethyl acetate:hexane (40:60, by volume) gradually changing to ethyl acetate:hexane (60:40, by volume) to give the title compound as a white solid (0.4 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccccc1Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1

Procedure:
(2-Methoxy-phenyl)-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and (4-trifluoromethylphenyl)boronic acid (33.0 mg, 0.174 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2e. The reaction product was isolated as a white solid (0.032 g, 53%). MP=184-186° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (dd, J=6.8, 0.9 Hz, 1H), 8.38 (dd, J=8.0, 1.3 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.63-7.58 (m, 2H), 7.08-6.88 (m, 4H), 3.92 (s, 3H). MS=385 (MH)+.
Reaction SMILES: Br[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 72 %

Procedure:
To a stirred solution of 736 mg (2.83 mmol) of ethyl 2-bromo-3-nitrobenzoate and 579 mg (3.1 mmol, 1.1 eq) of 1-tert-butyloxycarbonylpiperazine in n-butanol (6 mL) was added 330 mg (3.1 mmol, 1.1 eq) of Na2CO3. The mixture was heated to reflux for 4 h. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 744 mg (72%) of 4-(2-methoxycarbonyl-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 20% EtOAc/hexanes): Rf=0.5. 1H NMR (400 MHz, CDCl3): 7.67 (dd, J=8.2, 1.4 Hz, 1H), 7.62 (dd, J=8.2, 1.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 3.86 (s, 3H), 3.44-3.36 (m, 4H), 3.03-2.95 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:43][O:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[C:10]([NH:12][C@@H:13]2[C:41](=[O:42])[N:15]3[C:16]([C:38]([O-:40])=[O:39])=[C:17]([CH2:20][N+:21]4([CH3:37])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=5)[CH2:23][CH2:22]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:43][O:44][CH2:45][C:46]([OH:48])=[O:47])[C:10]([NH:12][C@@H:13]2[C:41](=[O:42])[N:15]3[C:16]([C:38]([O-:40])=[O:39])=[C:17]([CH2:20][N+:21]4([CH3:37])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=5)[CH2:23][CH2:22]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)CCN(C(=O)c2ccc(O)c(O)c2)CC1
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-methyl-4-(3,4-dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate dihydrochloride (syn isomer) (1.35 g) in dichloromethane (5.4 ml) and anisole (1.3 ml) was added dropwise trifluoroacetic acid (4 ml) at 25° C. The stirring was continued for 3 hours at the same temperature. The reaction mixture was poured into diisopropyl ether and the resulting precipitates were collected by filtration. The precipitates were dissolved in water and then adjusted to pH 3.0 with aqueous sodium bicarbonate. The resulting solution was subjected to column chromatography on Diaion HP-20 using 15% aqueous isopropyl alcohol as an eluent. The object fractions were lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[1-methyl-4-(3,4dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (320 mg).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[OH:11])([O-])=O.C([Cl:15])(=O)C>>[Cl:15][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[OH:11]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1O
Product: [O-][n+]1ccc(Cl)c(O)c1

Procedure:
The starting material was prepared by reaction of 4-nitro-3-hydroxy pyridine-N-oxide with acetyl chloride under reflux for 1 hour. The crude product was purified by rapid chromatography on silica gel using CH2Cl2 /MeOH 7:3 v/v as eluant to give 4-chloro-3-hydroxypyridine-N-oxide. Reduction of this compound with Raney nickel and hydrogen at ambient temperature for 2 hours in MeOH gave 4-chloro-3-hydroxypyridine. This compound was reacted with NaH in DMSO at 50°, the reaction mixture cooled and treated with 4-nitrobenzyl bromide for 1 hour. The reaction mixture was worked up with water and ether and the product treated with HCl/ether to give 4-chloro-3-(4-nitrobenzyloxy)pyridine hydrochloride. Reaction of the free base with excess methyl iodide at ambient temperature for 24 hours gave 4-chloro-1-methyl-3-(4-nitrobenzyloxy)pyridinium iodide. n.m.r. in d6DMSO-4.3(s, 3H); 5.6(s, 2H); 7.7(d, 2H); 8.3(d, 2H); 8.4(d, 1H); 8.7(d, 1H); 9.15(s, 1H).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8]S(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33](O)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[N:28][N:29]=2)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>CCOC(C)=O.O>[F:1][C@H:2]1[C@@H:7]([O:8][C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:32]=2[N:31]=[C:30]([C:27]2[N:25]4[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]4=[N:29][N:28]=2)[CH:39]=[CH:38]3)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1
Reactant: Oc1cccc2ccc(-c3nnc4ccc(F)cn34)nc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccc(F)cn45)nc23)[C@H](F)C1
Temperature: 90 °C
Yield: 81 %

Procedure:
A mixture of (trans)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (24 mg, 0.0807 mmol), 2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (23.8 mg, 0.0850 mmol) and Cs2CO3 (55.4 mg, 0.170 mmol) in DMA (425 μl, 0.0850 mmol) was heated to 90° C. for 16 hours. The mixture was transferred to a separatory funnel and diluted with EtOAc and water. The mixture was then extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a residue under reduced pressure to give the product without further purification (33 mg, 81% yield). MS APCI (+) m/z 481.9 (M+1) detected.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[O:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C@H:17]([OH:28])[C@@H:18]4[O:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 79.9 %

Procedure:
In 200 ml of tetrahydrofuran was dissolved 11.7 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one, followed by addition of 36 ml of a 1.0M solution of diisobutylaluminum hydride in toluene under ice-cooling. The mixture was stirred under ice-cooling for 15 minutes. Then, the reaction mixture was worked up in the same manner as Example 68 to recover 9.4 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3α-ol (yield: 80%) showing the following physical properties.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:20](=[O:21])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(CCC#Cc1ccccn1)C(=O)Cc1ccccc1
Yield: 74.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-phenylacetyl chloride (60 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 64 mg of N-methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3-ynyl)acetamide as a brown oil (Yield: 74%).
Reaction SMILES: C([C:3]1[C:4]([Br:11])=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Cl:9])C.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24]>CC(C)=O>[Br:11][C:4]1[CH:3]=[C:8]([Cl:9])[CH:7]=[CH:6][C:5]=1[O:10][CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24]
Reactant: CCc1c(Cl)ccc(O)c1Br
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCC1Oc1ccc(Cl)cc1Br
Temperature: 100 °C
Yield: 71 %

Procedure:
To a solution of ethyl 2-bromo-4-chlorophenol (10.9 g, 52.5 mmol) in acetone (105 mL) was added potassium carbonate (14.5 g, 105 mmol), followed by 2-chlorocyclopentanone (6.3 mL, 63 mmol). The mixture was refluxed at 100° C. overnight, then filtered through celite, concentrated in vacuo and purified by flash chromatography on silica gel (20% EtOAc in hexanes) to provide 2-(2-bromo-4-chlorophenoxy)cyclopentanone (516B) (10.8 g, 71.0%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.8 %

Procedure:
The compound (18.0 g) obtained in Example 103-2 was dissolved in chloroform (540 ml) and then added with manganese dioxide (chemically processed product) (118 g), followed by stirring at room temperature for 15 hours. The reaction solution was filtrated through Celite and the filtrate was then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (17.1 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([S:16][C:17]3[N:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[C:18]([C:19]4[N:31]=[N:32][NH:33][N:20]=4)=[CH:21][CH:22]=[CH:23][N:24]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(Sc3ncccc3C#N)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Sc3ncccc3-c3nn[nH]n3)c2)ccc(C(C)=O)c1O
Yield: 47.9 %

Procedure:
Using the procedure essentially as described for Example 1 using 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-nicotinonitrile (350 mg, 0.836 mmol), sodium azide (544 mg, 8.36 mmol), and triethylamine hydrochloride (1.15 g, 8.36 mmol) to yield the title compound as a tan solid (185 mg, 48%): 1H NMR (DMSO-d6) δ 0.796 (t, 3H), 1.45 (sextuplet, 2H), 2.56 (t, 2H), 2.58 (s, 3H), 5.29 (s, 2H), 6.73 (d, 1H), 7.38 (dd, 1H), 7.48 (m, 3H), 7.57 (s, 1H), 7.82 (d, 1H), 8.16 (d, 1H), 8.44 (dd, 1H), 12.84 (s, 1H); MS (esi negative) m/z 460 (m−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](OCC)=[O:12].[H-].C([Al+]CC(C)C)C(C)C.CO.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][OH:12]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: OC/C=C/c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a stirred solution of ethyl (2E)-3-(2,4-dichlorophenyl)acrylate (11.3 g, 46 mmol) in tetrahydrofuran at −10° C. was added diisobutylaluminium hydride (1.0 M in toluene, 100 ml, 0.11 mol) dropwise. After addition was complete, the reaction was cooled to −78° C. and methanol (40 ml) added dropwise. Ammonium chloride (sat. aq., 70 ml) was then added and the reaction allowed to warm to 0° C. After 15 min at 0° C. the reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was then filtered through a pad of hyflo supercel (washing well with ethyl acetate) and the concentrated to give the title compound (7.8 g) as pale yellow crystals. 1H NMR δ (ppm)(CDCl3): 7.44 (1 H, d, J=8.4 Hz), 7.36 (1 H, d, J=2.0 Hz), 7.19 (1 H, dd, J=2.0, 8.5 Hz), 6.93 (1 H, d, J=15.8 Hz), 6.36-6.28 (1 H, m), 4.35 (2 H, d, J=5.4 Hz), 1.84 (1 H, s).
Reaction SMILES: C[O:2][C:3]([CH:5]([NH:13][C:14]([C:16]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:44]=[CH:43][S:42][CH:41]=2)=[CH:34][C:17]=1[O:18][CH:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])[CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO>[C:3]([CH:5]([NH:13][C:14]([C:16]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:44]=[CH:43][S:42][CH:41]=2)=[CH:34][C:17]=1[O:18][CH:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:4])=[O:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(=O)NC(Cc1ccccc1)C(=O)OC)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C(=O)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 4-[2-(1-methoxycarbonyl-2-phenylethylcarbamoyl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate, thought to be the diastereomers (1R, 4RS), (0.48 g) in methanol (100 mL) is treated with 10% aqueous potassium carbonate solution (10 mL). The reaction mixture is stirred at room temperature for 18 hours and evaporated. The residue is dissolved in water (50 mL), the solution acidified to pH 1 by addition of 1 N hydrochloric acid and extracted with ethyl acetate (120 mL). The organic phase is washed with water (100 mL), brine (100 mL), dried over magnesium sulphate and evaporated. The semi-solid residue (0.44 g) is boiled with acetonitrile (20 mL), the mixture cooled to room temperature and filtered to remove 2-[2-hydroxy-4-(3-thienylmethoxy)benzoylamino]-3-phenylpropionic acid (0.047 g) as a white solid, m.p. 178-180° C. [Elemental analysis:- C,63.52; H,4.76; N,3.15%. Calculated :- C,63.46; H,4.82; N,3.52%]. The filtrate is evaporated to give 4-[2-(1-carboxy-2-phenylethylcarbamoyl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the diastereomers (1R, 4RS), (0.3 g), as an oily semi-solid. [Elemental analysis:- C,66.54; H,5.45; N,2.35%. Calculated :- C,67.00; H,5.45; N,2.44%].
Reaction SMILES: C(OCC)(=O)C.C(OC([N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][C:24](=[O:40])[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:29][CH2:28]3)=[O:26])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)=O)(C)(C)C>Cl>[CH2:33]([CH:30]1[CH2:29][CH2:28][N:27]([C:25](=[O:26])[C:24]([NH:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[NH:14][CH2:15][CH2:16]3)=[O:40])[CH2:32][CH2:31]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCN2)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a solution of 10 ml of 2.5 M hydrochloric acid in ethyl acetate 0.9 g (2.0 mmol) of 5-[2-(4-benzyl-piperidin-1-yl)-2-oxo-acetylamino]-2,3-dihydro-indol-1-carboxylic acid tert-butyl ester is added. The reaction mixture is stirred for 3 hours at 20° C., then concentrated. The product is transformed into base form with 2 M sodium carbonate solution, extracted with chloroform, the organic layer is concentrated and the residue is dried to yield 0.45 g (64.1%) of the title compound. Melting Point: 152° C.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=1S(Cl)(=O)=O.[OH-].[Na+].Cl>O>[Br:7][C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Br)s1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Br)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 172.9 %

Procedure:
27.5 g of sodium sulfite are dissolved in 300 ml of water, and a total of 35 g of 5-bromo-4-chlorosulfonylthiophene-2-carboxylic acid is added, in portions, at 70° C., with a pH of 9-11 being maintained using 10N NaOH. The mixture is subsequently stirred at 70° C. for 2 h and then adjusted to pH=1 with HCl, after which the product is filtered off with suction. 41 g of colorless crystals are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH3:17])[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C@H:11]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH3:17][O:16][C@H:15]1[C:14]([CH3:18])([CH3:19])[CH2:13][CH2:12][C@@H:11]([O:20][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCBr
Reactant: CO[C@@H]1[C@H](COCc2ccccc2)[C@H](O)CCC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCO[C@@H]1CCC(C)(C)[C@H](OC)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of (1R,2R,3R)-2-(benzyloxymethyl)-3-methoxy-4,4-dimethylcyclohexanol (7 mg) and sodium hydride (5 mg, 60% dispersion in oil) and n-octyl bromide (20 ml) in dry N,N-dimethylformamide (0.3 ml) was stirred for 2 hrs at room temperature. The mixture was cooled to 0° C., and the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography (using n-hexane:ethyl acetate=10:1 as an eluent) gave benzyl [(1R,2R,6R)-2-methoxy-3,3-dimethyl-6-octyloxycyclohexyl]methyl ether (8 mg, 83%).