Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[NH:44][C:43]([CH3:45])=[N:42][N:41]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].O1CCOCC1.P([O-])([O-])(O)=O.[K+:57].[K+]>[Pd].C(O)C>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[NH:44][C:43]([CH3:45])=[N:42][N:41]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:57]
Reactant: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)[nH]1
Agent: [Pd]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nnc(SC2=C(C(=O)[O-])N3C(=O)[C@@H](C(C)(C)O)[C@H]3C2)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-4H-1,2,4-triazol-3-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg) and 5% palladium on activated carbon (50 mg) in 0.048M aqueous dipotassium hydrogen phosphate (4.85 ml), ethanol (0.5 ml), and dioxane (6.0 ml) was shaken for 2 hours under a hydrogen atmosphere (40 psi) at ambient temperature. After the catalyst was filtered off, the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion CHP-20P", eluting with water (100 ml) and 5% aqueous isopropyl alcohol (100 ml). The fractions, whose UV spectra showed λmax 292 nm, were combined and lyophilized to give potassium (5R, 6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl- 4H-1,2,4-triazol-3-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (13.2 mg) as a yellow powder.
Reaction SMILES: [C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:17]([OH:20])(=[O:19])[CH3:18]>C([O-])(=O)C.[Hg+]>[C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][CH:3]([O:20][C:17](=[O:19])[CH3:18])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.8 g (24.4 mmol, 1.5 eq) of mercury acetate are added to a solution of 4 g (16.3 mmol, 1 eq) of (1) dissolved in 100 ml of acetic acid. The reaction mixture is stirred for 1 day at ambient temperature, and then an additional 1 g (3.13 mmol, 0.2 eq) of mercury acetate is added. After stirring for a further 1 day at ambient temperature, the reaction is complete. The acetic acid is evaporated off under high vacuum and the residue is taken up in ether. The organic phase is extracted with a saline solution and then dried over Na2SO4, filtered and evaporated under reduced vacuum, to give a yellow oil. The crude product is chromatographed on silica gel, to give a colorless oil (4.4 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]=O>>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: Cc1cccc(CCC=O)c1C
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1cccc(CCC2NCCn3c(C)nc(C)c32)c1C

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,3-dimethyl-phenyl)-propionaldehyde. LC-MS: tR=0.61 min.; [M+H]+=284 g/mol.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:4]=1>CO>[NH2:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:4]=1
Reactant: Clc1cc(Nc2ccc3cc[nH]c3c2)ncn1
Reactant: N
Solvent: CO
Product: Nc1cc(Nc2ccc3cc[nH]c3c2)ncn1
Temperature: 130 °C
Yield: 78 %

Procedure:
A 7N ammonia in methanol solution (75 ml) was added to 6-chloro-4-(1H-6-indolylamino)pyrimidine (1.229 g, 5.0 mmol); and the reaction mixture was heated in a sealed tube at 130° C. for 6 days. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); diethyl ether was added to the residue to crystallize; the crystals were filtered off, and washed with diethyl ether, and dried under aeration to yield the title compound (883 mg, 3.9 mmol, 78%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:28])[C:25](O)=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[C:66]([O:70][NH2:71])([CH3:69])([CH3:68])[CH3:67]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:28])[C:25]([NH:71][O:70][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:26])(=[O:17])=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(C(=O)O)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)ON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)ONC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R,4R)-4-(4-(Benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylic acid (715 mg, 1.76 mmol) was dissolved in DMF (8 mL), and BOP reagent (1.01 g, 2.29 mmol, 1.3 eq), N,N-diisopropylethylamine (1.2 mL, 7.04 mmol, 4.0 eq) and O-(tert-butyl)hydroxylamine hydrochloride (332 mg, 2.64 mmol, 1.5 eq) were sequentially added. The reaction was stirred at room temperature overnight and then diluted with ethyl acetate (200 mL), and washed with water (3×50 mL). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated affording (3R,4R)-4-(4-(benzyloxy)phenylsulfonamido)-N-tert-butoxy-3-methyl-tetrahydro-2H-pyran-3-carboxamide as white fluffy powder that was used in the next step without purification. MS: (M+Na)+=499.0; (M−H)−=475.2.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([C:38](OCC)=[O:39])[C:33](OCC)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([CH2:33][OH:34])[CH2:38][OH:39])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(CO)CO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
A solution of diethyl [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]malonate (100 mg) in tetrahydrofuran (1.5 mL) was added to a suspension of lithium aluminum hydride (15 mg) in tetrahydrofuran (1.5 mL) under ice-cooling, and the mixture was stirred for 2 hr. Lithium aluminum hydride (30 mg) was further added, and the mixture was stirred with heating under reflux overnight. After cooling to room temperature, the reaction mixture was diluted with tetrahydrofuran, and the reaction was quenched with sodium sulfate decahydrate. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was subjected to preparative HPLC to give the title compound (15 mg, yield 15%) as a yellow amorphous solid. MS: 511 (MH+).
Reaction SMILES: COC1C=CC(C2SC3C=C(OC)C=CC=3C=2)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:38][C:39]1[CH:40]=[C:41]([NH:54][C:55]2[CH:60]=[C:59]([O:61]C)[CH:58]=[CH:57][C:56]=2[C:63]2[S:67][C:66]3[CH:68]=[C:69]([O:72]C)[CH:70]=[CH:71][C:65]=3[CH:64]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>>[F:38][C:39]1[CH:40]=[C:41]([NH:54][C:55]2[CH:60]=[C:59]([OH:61])[CH:58]=[CH:57][C:56]=2[C:63]2[S:67][C:66]3[CH:68]=[C:69]([OH:72])[CH:70]=[CH:71][C:65]=3[CH:64]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(-c2cc3ccc(OC)cc3s2)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc(-c2cc3ccc(O)cc3s2)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 46.4 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenyl]amine (322 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (141 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH:10]([C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OC(=O)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:11][CH:12]([C:14](=[O:16])[O:19][C:17]2=[O:18])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC(C1)C(=O)OC2=O

Procedure:
A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated 3× times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6](=O)[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=1)[CH3:2].O=P(Cl)(Cl)[Cl:27].C(=O)([O-])O.[Na+]>>[Cl:27][C:6]1[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=[C:4]([S:3][CH2:1][CH3:2])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1nc2c(sc3nc(-c4ccccc4)cc(C)c32)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCSc1nc(Cl)c2sc3nc(-c4ccccc4)cc(C)c3c2n1
Temperature: 0 °C
Yield: 22.3 %

Procedure:
1.23 g (3.5 mmol) 2-ethylthio-9-methyl-7-phenyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidin-4-one is refluxed in 10 ml (10.9 mol) phosphoroxychloride for 6 h. Then, the product is poured onto about 100 g ice water and neutralized with saturated sodium hydrogen carbonate solution. The precipitate is sucked off, washed with about 100 ml water, dried and purified by means of flash chromatography (dichloromethane/petroleum ether 5:1). 0.29 g (22%) 4-chloro-2-ethylthio-9-methyl-7-phenyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine is obtained.
Reaction SMILES: O.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[CH3:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O>CO.CCOCC>[CH3:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]
Reactant: COCc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: COCc1ccccc1N
Reaction time: 1 h
Yield: 101.8 %

Procedure:
528 g of 21.8% strength Na2 [Fe(CO)4 ] solution (0.6 mol; 1 kg of the solution contains 633 g of water, 218 g of Na2 [Fe(CO)4 ], 108 g of Na2CO3 and 41 g of NaOH) are added dropwise to 101 g (0.6 mol) of o-methoxymethylnitrobenzene (Example 3a) in 1 l of methanol at 20°-30° C. Stirring is carried out for 1 hour at room temperature, after which the reaction mixture is diluted with ether. A brown oil separates out in the reaction vessel. The total reaction mixture is poured onto a silica gel column and is eluted with ether. Thereafter, the ether phase is evaporated, the residue is taken up in methylene chloride and the solution is dried over MgSO4. It is filtered under suction over silica gel and the solvent is then evaporated off under reduced pressure. The residue is purified by column chromatography with hexane and methylene chloride. 83.8 g of o-methoxymethylaniline are obtained as a brown oil, which is directly reacted further.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+].C1COCC1.Cl[C:46]([O:48][C:49]1[CH:58]=[CH:57][C:52]([C:53]([O:55]C)=[O:54])=[CH:51][CH:50]=1)=[O:47]>O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:46]([O:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=2)=[O:47])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 192 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 157 mg of sodium hydrogen carbonate were added 3 mL of THF and 1.5 mL of water, followed by addition of 133 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). It was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to 327 mg of the obtained residue were added 4 mL of THF, 2 mL of methanol, and 2.5 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized by addition of 2.6 mL of 1 M hydrochloric acid, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 228 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][NH:49]2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][N:49]2[C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1
Reactant: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (317.0 mg, 0.660 mmol), methyl 3-chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (172.0 mg, 0.635 mmol), Et3N (105 ul, 0.756 mmol) in DMF (2.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 3-chloro-2-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a brownish oil. To a stirred solution of this compound in THF (6.0 mL) and H2O (2.0 mL) was added LiOH (45.3 mg, 1.89 mmol), and the reaction mixture was stirred for 5 hr at room temp. The mixture was diluted with n-hexane and extracted with 1N-NaOH. The aqueous layer was acidified by the addition of 1N HCl and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure and the obtained crude solid was recrystallized from n-hexane-EtOAc—EtOH to afford 242.2 mg (70%) 47 as an orange crystalline powder. mp 122-125; IR (KBr) 3354, 1709, 1593, 1535, 1454, 1257 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.67-2.03 (m, 4H), 2.50 (s, 3H), 3.33-3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27-4.31 (m, 2H), 4.42-4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87-6.95 (m, 3H), 7.11-7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 553 (M++1); Anal. Calcd. for C28H29ClN4O6: C, 60.81; H, 5.29; N, 10.31. Found: C, 60.98; H, 5.50; N, 9.46.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:2]=1.[H][H]>CCO.C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:2]1
Reactant: CCOP(=O)(OCC)c1cccnc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1CCCNC1

Procedure:
Diethyl pyridin-3-ylphosphonate was dissolved in EtOH-acetic acid, to which platinum oxide was added, for stirring under 3.4 kgf/cm2 hydrogen for 120 hours, to obtain diethyl piperidin-3-ylphosphonate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[CH:8][C:9]([CH:10]([OH:11])[CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=2)=[CH:2]1
Reactant: O=Cc1ccc(-c2ccoc2)nc1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C(O)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 47b (160 mg, 0.92 mmol) and isopropylmagnesium chloride (0.92 mL, 1.85 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Yellow solid. Yield: 53 mg, 27%. MS (ESI): m/z=218.30 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH:20]([CH3:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5]>C1COCC1.[OH-].[Na+].CO>[CH3:30][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH:20]([CH3:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])([CH3:5])[C:3]([OH:31])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(COc1ccccc1)Oc1c(C(=O)NC(C)(C)C(=O)O)ccc2ccccc12

Procedure:
110 mg 2-methyl-2-{[1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester in 1 ml THF, 0.3 ml of 2 M sodium hydroxide and 0.3 ml methanol were heated under reflux for 2 h. The organic solvents were then removed in vacuo, and the residue was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate and concentrated. After purification by RP-HPLC 10 mg of 2-methyl-2-{[1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-propionic acid were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CBr
Yield: 49.3 %

Procedure:
5.34 g (30 millimoles) of methyl 2-methylphenylglyoxylate and 5.34 g (30 millimoles) of N-bromosuccinimide in 1000 l of tetrachloromethane are exposed to a 300 W Hg vapor lamp for one hour. The organic phase is then washed once with water and three times with sodium bicarbonate solution and is dried over sodium sulfate/sodium carbonate. After the solution has been evaporated down, the crude product is chromatographed over silica gel using 1:9 methyl tert-butyl ether/n-hexane. 3.8 g (49%) of the abovementioned compound are obtained as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]([O:21][CH3:22])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]([O:21][CH3:22])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C(OC)C(=O)O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(OC)C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.1 %

Procedure:
To a stirred solution of (RS)-(3-benzyloxy-4-methoxy-phenyl)-methoxy-acetic acid (0.923 g) at rt in ethanol was added 10% Pd/C. The mixture was then stirred at rt under a hydrogen atmosphere for 17 h. The catalyst was filtered off and washed with dichloromethane. The filtrate was concentrated (rotavapor) to give (RS)-(3-hydroxy-4-methoxy-phenyl)-methoxy-acetic acid (0.642 g) as an orange gum.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].C[O:8][C:9]([C:11]1[C:12]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:13][S:14][C:15]=1[NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=O>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][S:23][C:12]2[C:11]([C:9]([NH2:6])=[O:8])=[C:15]([NH:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[S:14][N:13]=2)=[CH:26][CH:27]=1
Reactant: [NH4+]
Reactant: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ncccn1
Agent: C[Al](C)C
Agent: [Cl-]
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ncccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
Trimethyl aluminum (2M/toluene, 2.55 mL, 5.1 mmol) is added to a dry flask containing ammonium chloride (272.3 mg, 5.1 mmol). The solution is then allowed to stir for 30 min and is added to a dry flask containing compound 21 (100 mg, 0.26 mmol). The reaction is then heated to 80° C. for 4 hours and then cooled to room temperature. The reaction is then carefully quenched with 1 N HCl and extracted with EtOAc (×3). The combined organics are dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (20%→50% EtOAc/methylene chloride) provides 3-(4-Chloro-benzylsulfanyl)-5-(pyrimidin-2-ylamino)-isothiazole-4-carboxylic acid amide (16.2 mg, 17%) in addition to the starting material 21 (36.6 mg). 1H NMR (d6 DMSO): δ 11.61 (1H, br. s), 8.73 (2H, d, J=5.0 Hz), 7.43 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.15 (1H, dd, J=5.0, 5.0 Hz), 4.46 (2H, s). LRMS (M+): 378.1, (M−): 376.0.