Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH2:30][CH2:31][CH3:32])=[N:23][C:24]=2Cl)(=O)C.[CH2:33]([NH2:35])[CH3:34]>O1CCOCC1.O>[CH2:33]([NH:35][C:24]1[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=[C:22]([S:29][CH2:30][CH2:31][CH3:32])[N:23]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4])[CH3:34]
Reactant: CCCSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reactant: CCN
Solvent: C1COCCO1
Solvent: O
Product: CCCSc1nc(NCC)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-(propylthio)purine (1.3 g) and ethylamine (1.6 ml) in dioxane (30 ml) and water (30 ml) were heated in a sealed autoclave at 110° for 20 hours. On cooling to room temperature, evaporation gave a residue which was recrystallised from ethyl acetate. Further purification by chromatography (SiO2, methanol:ethyl acetate, 1:15 as eluant) gave the sub-title compound (0.46 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.C[O:27][C:28]([C@:30]1([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:34][CH2:33][CH2:32][N:31]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=O>C1COCC1>[C:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C:30]1([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:12]([CH3:13])[CH3:14])[CH:6]=[CH:5]2)=[O:27])=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)[C@]1(Cc2ccccc2)CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3(Cc4ccccc4)CCCN3C(=O)OC(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To a stirred solution of 5-bromo-1-triisopropylsilanyl-1H-indole (0.55 g, 1.57 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added tert-butyllithium (2.02 mL of 1.55 M solution in pentanes, 3.13 mmol) dropwise. After one hour, the reaction mixture was added rapidly to a cold (−78° C.) solution of (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.50 g, 3.13 mmol) in THF (10 mL). The reaction mixture was stirred at −78° C. for one hour, then warmed to room temperature and stirred for two hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) then extracted with EtOAc. The combined extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 0-20% EtOAc in hexanes) gave 2-benzyl-2-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.259 mmol, 16%) as a colourless gum.
Reaction SMILES: CC(C)(C)C[Mg]Cl.ClCC(C)(C)C.[Mg].[CH3:15][C:16]([CH3:35])([CH3:34])[CH2:17][Cr-:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCC>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][Cr:18]([CH2:17][C:16]([CH3:35])([CH3:34])[CH3:15])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)C[Cr-](CC(C)(C)C)(CC(C)(C)C)CC(C)(C)C
Agent: CC(C)(C)CCl
Agent: CC(C)(C)C[Mg]Cl
Agent: [Mg]
Solvent: CCCCCC
Product: CC(C)(C)C[Cr](CC(C)(C)C)(CC(C)(C)C)CC(C)(C)C

Procedure:
CrCl3(THF)3 (a product of Aldrich Co.) and 2,2-dimethylpropyl magnesium chloride (synthesized from 1-chloro-2,2-dimethylpropane, a product of Aldrich Co. and magnesium, a product of Wako Pure Chemicals Co.) were reacted according to a method described in J. Chem. Soc., Dalton Trans., 770 (1973) to prepare tetrakis(2,2-dimethylpropyl)chromium(III). This compound was dissolved in distillation-purified hexane to obtain a solution of 0.10 mol/liter, 5.20 g/liter.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][CH2:17][CH2:18][CH:19]([NH2:23])[C:20]([OH:22])=[O:21].CC#N>O>[C:20]([CH:19]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][CH2:17][CH3:16])([OH:22])=[O:21]
Reactant: CCCC(N)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CC#N
Solvent: O
Product: CCCC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O
Yield: 15 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-2-aminopentanoic acid to provide the title compound in 15% yield as yellow needles (flash chromatography on SiO2, eluent MeCN, H2O, AcOH-20, 1, 0.3).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C@@H:9]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:8][C@@H:9]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc([N+](=O)[O-])c3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc([N+](=O)[O-])c3)OC(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
Acetic anhydride (1.67 ml, 17.6 mM) is added to a solution of (S)-2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)-1-(3-nitrophenoxy)propane (1.99 g, 4.4 mM) (Example 27) in CH2Cl2 (4 ml) and pyridine (2 ml). The mixture is maintained in agitation for 21 hours at room temperature. Then it is treated with 1N HCl, followed by a saturated aqueous NaHCO3 solution. The two phases are separated and the organic phase dried over Na2SO4, filtered and the solvent removed under vacuum. An oil is obtained from which the product (S)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]-1-(3-nitrophenoxy)propane is isolated (yield of 69%) by column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate=1:1). [α]D=−10.0 (c 1.04, CHCl3). FT-IR (neat): 3092, 2930, 2850, 1740, 1597, 1576, 1531, 1499, 1458, 1373, 1350, 1329, 1307, 1259, 1234, 1164, 1095, 944, 805, 737 cm−1. 1NMRs (400 MHz CDCl3, δ): 7.82-7.79 (m, 1H, aromatic proton); 7.68-7.65 (m, 3H, aromatic protons); 7.42-7.38 (t, 1H, J=8.2 Hz, aromatic proton); 7.21-7.18 (dd, 1H, J=8.4 Hz, 2.6 and 0.9 Hz, aromatic proton); 7.00-6.97 (m, 2H, aromatic protons); 5.30-5.20 (m, 1H, CHOAc); 4.17-4.13 (dd, 1H, J=10.3 and 3.5 Hz, CH2OAr), 4.12-4.08 (dd, 1H, J=10.3 and 6.4 Hz, CH2OAr); 3.86 (s, 3H, OCH3); 3.10-2.90 (m, 4H, 2 CH2N of piperazine); 2.70-2.50 (m, 6H, 2 CH2N of piperazine and CHOHCH2N); 2.04 (s, 3H, CH3CO). 13C NMRs (100 MHz CDCl3, δ): 170.29, 163.03, 158.88, 149.03, 129.99, 129.81, 126.92, 121.81, 116.15, 114.21, 108.63, 94.40, 68.08, 57.36, 55.56, 52.74, 46.01, 21.04. MS-ESI m/z (%): 494 [M+H]+ (22); 516 [M+Na]+ (100). MS-MS (516): 516 (3), 435 (22), 434 (100), 295 (10), 269 (26), 263 (13). Anal. Calc. for C22H27N3O8S: C, 53.55; H, 5.48; N, 8.52. Found: C, 53.51; H, 5.41; N, 8.69.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1.[NH2:34][CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccn3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, the title compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=459.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.C(I)I.[CH2:16]([N:23]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=1)[CH:24]([CH2:27][CH:28]=[CH2:29])[CH2:25][OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:16]([N:23]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=1)[CH:24]([CH2:27][CH:28]1[CH2:1][CH2:29]1)[CH2:25][OH:26])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CCC(CO)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: OCC(CC1CC1)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 25 °C

Procedure:
Diethylzinc (0.064 g, 0.526 mmol) was added to a flask containing CH2Cl2 (2 mL) at 0° C. A solution of TFA (0.052 ml, 0.526 mmol) in CH2Cl2 (1 ml) was slowly added to the flask containing diethylzinc over 20 min. A solution of CH2I2 (0.042 mL, 0.526 mmol) in CH2CH2 (1 mL) was added next over 20 min. followed by addition of 2-[benzyl(3-chloro-4-fluorophenyl)amino]pent-4-en-1-ol (7-5, 0.028 g, 0.088 mmol) in CH2Cl2 (1 mL). The resulting solution was warmed to 25° C. The reaction mixture was diluted with NaHCO3 (sat. aq) and extracted with CH2Cl2 (3×5 ml). The combined organic layers were dried with NaSO4, filtered, and concentrated. The crude residue was purified by reverse phase liquid chromotography (Semi Prep YMC C-18 Reverse Phase Column 5% CH3CN/H2O to 95% CH3CN/H2O with 0.1% TFA present) to yield 2-[benzyl(3-chloro-4-fluorophenyl)amino]-3-cyclopropylpropan-1-ol (9-2). MS 334.2 found 334.8 (M+H+) required.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8]2.O.[OH-].[Na+]>Br>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2ccc(C(F)(F)F)nc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc2ccc(C(F)(F)F)nc12
Yield: 99.1 %

Procedure:
A solution of 8-methoxy-2-trifluoromethylquinoline (10.0 g) in 48% hydrobromic acid (40 ml) was stirred at reflux overnight. The reaction mixture was poured into water (200 ml) and the pH adjusted to 12.5 using 46-48% sodium hydroxide solution. After extraction with dichloromethane (2×25ml) the aqueous layer was acidified to pH 5.3 by the addition of 37% hydrochloric acid solution. The mixture was then extracted using dichloromethane (2×100 ml) and the combined organic extracts washed with water, dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (9.3 g) as a white solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)[C:11]2[C:16]([C:17]=1[O:18]C(=O)C)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+].CO>>[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]([OH:18])=[C:8]([C:6]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:7])[N:9]=2)=[CH:28][CH:27]=1)(=[O:32])[CH3:31]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(Oc2ccc(NC(C)=O)cc2)c2ccccc2c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(Oc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)cc1
Yield: 64 %

Procedure:
A mixture of 4-Acetoxy-1-(4-acetylamino-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (150 mg, 0.34 mmol), glycine (290 mg, 3.4 mmol), and 7.8 ml of a 0.5 N solution of sodium methoxide in methanol (3.9 mmol) was refluxed over the weekend with stirring. Then the solvent was evaporated in vacuo and the residue dissolved in 25 ml of water. The pH of the solution was subsequently adjusted to about 2 and the resulting slurry was extracted with ethyl acetate (3×30 ml). The combined extracts were dried over MgSO4 and evaporated in vacuo. Recrystallization of the residue from methanol/CH2Cl2 gave 86 mg of the title compound; MS-(+)-ion: M+1=396.15.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[S:21])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CN)CC1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CNC(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 3.1 parts of 1-acetyl-4-piperidinemethanamine, 3.4 parts of 1-chloro-4-isothiocyanatobenzene and 90 parts of tetrahydrofuran was stirred for 3 hours at room temperature. The reaction mixture was evaporated, yielding 6.5 parts (99.7%) of N-[(1-acetyl-4-piperidinyl)methyl]-N'-(4-chlorophenyl)thiourea as a residue (intermediate 14).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[CH:7]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8](=C)[CH2:9][S:10][C@H:5]12)[CH3:3].C(Cl)Cl.[O:33]=[O+][O-].CSC>O=O>[OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[C:7]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[C:8]([OH:33])[CH2:9][S:10][C@H:5]12)[CH3:3]
Reactant: C=C1CS[C@@H]2C(C(C)O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: CC(O)C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 0.33 h

Procedure:
Benzhydryl 7-(1-hydroxyethyl)-3-methylene-cepham-4-carboxylate (4.6 g.) is dissolved in 500 ml. of CH2Cl2, cooled to -78° and treated with a stream of ozone in oxygen until a blue color persists in the reaction mixture. After 1 minute at -78° the reaction mixture is treated with 5 ml. of dimethyl sulfide and the reaction mixture is allowed to stand at -78° for 20 min. followed by 1 hour at 25° C. The solvent is removed under reduced pressure to give the crude benzhydryl 7-(1-hydroxyethyl)-3-hydroxy-3-cephem-4carboxylate.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:31])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:29]([O:28][C:26](=[O:27])[C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:18]([C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][NH:8]3)=[CH:13][CH:14]=2)=[O:31])=[CH:25][CH:24]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1

Procedure:
A solution of 7-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.1 g, 2.5 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature for 2 hours. The solvent was then removed and the residue redissolved in dichloromethane and washed with saturated sodium hydrogencarbonate. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester as a white solid, 790 mg (97%). MS (ISP): m/e=325.4 (M+H+.); δH (300 MHz; CDCl3) 8.59 (1H, s), 7.98 (2H, d), 7.77 (1H, s), 7.69 (2H, d), 7.48 (1H, d), 7.09 (1H, d), 4.37 (2H, q), 3.44 (2H, m), 2.79 (2H, t), 2.08 (2H, m), 1.40 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21]C(O)CO.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1
Reactant: COCCOCCOCCOCC(O)CO
Reactant: COc1cscc1OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCOCCOCCOCC1COc2cscc2O1
Temperature: 100 °C

Procedure:
A transetherification reaction between 3,4-dimethoxythiophene (12.9 g, 89 mmol) and {2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxymethyl}-1,2-ethanediol (24.5 g) in toluene (150 mL) was performed by heating (at 100° C.) a mixture of these compounds under a continuous nitrogen flow for 24 h. Subsequently, the reaction mixture was poured into methylene chloride (200 mL) and the organic phase was washed with a 1M aqueous sodium hydrogen carbonate solution, an aqueous concentrated sodium chloride solution, dried with anhydrous magnesium sulphate and concentrated. This resulted in a viscous oil. Pure 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxymethyl}-2,3-dihydro-thieno[3,4-b][1,4]dioxine was finally obtained by vacuum distillation.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-])=O)=[O:4].O>CO>[NH2:17][C:9]1[CH:10]=[C:11]([S:14][C:15]#[N:16])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[S:20]
Reactant: COC(=O)NC(=S)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1N
Yield: 26.6 %

Procedure:
A stirred mixture of 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-thiocyanatobenzene (27.0 g.), ferrous chloride tetrahydrate (5.85 g.), methanol (450 ml.) and water (100 ml.) was brought to reflux and treated with reduced iron powder (29.7 g.) portionwise during 5 minutes. The mixture was heated at reflux for one hour, methanol (250 ml.) was added, and the boiling solution was filtered hot. The filtrate was evaporated to dryness and the residue was extracted with boiling methanol (3× 500 ml.). The extract was evaporated and the residue was recrystalised from methyl ethyl ketone (removing some undissolved material by filtration of the hot solution) to give 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-thiocyanatobenzene (6.5 g.), m.p. 174°-176° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)[CH3:41].CCOC(/N=N/C(OCC)=O)=O>>[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:48][CH:47]=1)[CH3:41]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)OCC
Yield: 17.7 %

Procedure:
Reaction of 3,3-bis-(4-methoxyphenyl)-prop-2-en-1-ol (1.62 g, 5.99 mmol), triphenylphosphine (2.88 g, 10.98 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.19 g, 4.99 mmol) and diethy lazodicarboxylate (1.92 g, 11.04 mmol) in an identical manner to example 1 gave the title compound (0.434 g, 17%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.[C:11](Cl)([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1noc2ccccc12
Product: O=C(Nc1noc2ccccc12)OCC(Cl)(Cl)Cl

Procedure:
Using General Method A, benzo[d]isoxazol-3-amine (500 mg, 3.37 mmol) and Troc-Cl (1.185 g, 5.59 mmol) were combined, purified by column chromatography (ethyl acetate/hexanes), triturated with hexanes (30 mL), filtered and dried to afford 2,2,2-trichloroethyl benzo[d]isoxazol-3-ylcarbamate. 1H NMR (300 MHz, DMSO-d6): δ 5.15 (s, 2 H), 7.50 (t, 1 H), 7.77-7.83 (m, 2 H), 8.16 (d, 1 H), 11.51 (s, 1 H); MS (ESI) m/z: 310.9 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][OH:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.C1([Se](O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Agent: O=[Se](O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 70 °C

Procedure:
49a (0.68 g, 2.26 mmol) in toluene (5 ml) was added benzeneseleninic acid (0.64 g, 3.39 mmol). The mixture was heated to 70° C. for 5 hours. After cooling the product was filtered off and washed with warm toluene and CH2Cl2 successively. Yield 0.58 g (86%). Mp 00°-202° C.
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: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(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.