Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:28][CH:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:26][CH3:27]>>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:39]2[CH:38]=[CH:37][C:36]([CH2:35][CH:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)OCCN1CCOc2ccccc21
Reactant: CCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OCC
Yield: 52.6 %

Procedure:
The title compound (0.4 g, 52%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g, 1.78 mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol) using conditions analogous to that described in preparation 2.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CN(C=O)C.[H-].[Na+].O([CH:18]=[CH:19][C:20](=[N:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([S:3][CH:18]=[CH:19][C:20](=[N:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSC=CC(=Nc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethanethiol (0.11 ml) was dissolved to DMF (3 ml), and sodium hydride (60% in oil: 60 mg) was added under ice-cooling, and stirred for 30 minutes at the same temperature. Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to DMF (2 ml), and the obtained solution was added to the above mentioned thiolate solution under ice-cooling, and stirred for two hours at the same temperature and for two hours at room temperature. Ethyl acetate (100 ml) was added to the reaction solution, and it was successively washed with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-ethylthio-N-phenylacrylimidate (0.14 g) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Yield: 40 %

Procedure:
A solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (237.5 mg, 0.68 mM) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 20 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 89.7 mg (40%) of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.9 (m, 7H), 6.65 (m, 2H), and 5.75 (s, 2H). IR (KBr, cm1) 3395, 3192 (br), 1621, 1599, 1580, 1564, 1491, 1455, 1334, 1261, and 774. MS (ES) m/e 333, 335.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Br:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19]>CN(C=O)C>[Br:15][C:10]1[CH:9]=[C:8]([S:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:19])(=[O:7])=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)NC(C)C)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of N-isopropyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks; 200 mg; 0.68 mmol) in anhydrous DMF (4 mL) was treated with NaH (33 mg; 0.82 mmol) and stirred at RT for five minutes. The resulting mixture was treated with iodomethane (43 μl; 0.68 mmol) and the reaction mixture was stirred for 16 hours. The mixture was treated again with iodomethane (21 μl; 0.34 mmol) and the reaction mixture was stirred at RT for 24 hours. The mixture was quenched with an aqueous (5 N) solution of NaOH and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, concentrated and purified flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as a colorless sticky solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.N1C=CN=C1.Cl[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c2cc(O)ccc2o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 5-hydroxy-1,3-benzoxazol-2(3H)-one (Itoh, et al., J. Org. Chem. 2002 (67):7424-7428) (1.00 g, 6.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added imidazole (0.54 g, 7.9 mmol), followed by chloro-tert-butyldimethylsilane (1.10 g, 7.3 mmol). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0 to 50% gradient) to afford 5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one (1.53 g, 87%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.04 (br s, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.60-6.53 (m, 2H), 0.98 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34]O)[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[N:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: COc1ccc2ncc(C(=O)O)cc2n1
Reactant: OC[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-Methoxy-[1,5]naphthyridine-3-carboxylic acid (100 mg, 0.44 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol (129 mg, 0.44 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (93 mg, 0.48 mmol, 1.10 eq) and 4-(dimethylamino)pyridine (81 mg, 0.66 mmol, 1.50 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-[1,5]naphthyridine-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethyl ester as an off-white semisolid (33 mg, 15% yield).
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18](O)=[O:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]1([S:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18]([Cl:25])=[O:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 100 %

Procedure:
The 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (12) (5.582 g, 16.7 mmol) prepared above was refluxed with dimethylformamide (1 drop), thionyl chloride (3.57 ml, 50 mmol) and toluene (22 ml) for 1.5 hours. When the solvent was removed under reduced pressure, 5.89 g of the objective compound (6) was obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[OH:27][CH2:28][C@@H:29]1[O:34][CH2:33][CH2:32][N:31]([C:35]2[S:36][CH2:37][C:38](=[O:40])[N:39]=2)[CH2:30]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:37]3[S:36][C:35]([N:31]4[CH2:32][CH2:33][O:34][C@@H:29]([CH2:28][OH:27])[CH2:30]4)=[N:39][C:38]3=[O:40])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1CSC(N2CCO[C@@H](CO)C2)=N1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1N=C(N2CCO[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2(R)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2(R)-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following General Procedure D.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:18])[CH2:3][CH2:4][CH:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)CC=C(c2cccn3nc(N)nc23)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCC(c2cccn3nc(N)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution 8-(4,4-dimethyl-cyclohex-1-enyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (30 mg, 0.124 mmol) in methanol (4 mL) was added 10% Pd/C (30 mg), and the reaction mixture was allowed to stir under hydrogen balloon atmosphere at 25° C. for 2 hours. The reaction mixture was filtered through a bed of celite, and the filtrate was evaporated off in vacuo to get the title compound (30 mg, 99%) as a white solid which was used in next step without further purification. MS ISP (m/e): 245.0 (100) [(M+H)+].
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[OH:4][CH2:3][CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1)=[S:14])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(N)CO)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: Cc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1

Procedure:
The title compound was prepared with 2-amino-2-(p-tolyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 71%): mp 145-156° C.; 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.12 (d, J=6.8 Hz, 2H), 8.05 (d, J=2.2 Hz, 2H), 7.65 (d, J=7.4 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.24-7.23 (m, 2H), 7.18-7.16 (m, 2H), 5.60 (s, 1H), 3.90-3.84 (m, 2H), 2.34 (s, 3H) (NH, OH not observed); ESIMS m/z 514 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:12][CH2:11][C@H:10]([O:13][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 4.5 h
Yield: 68.4 %

Procedure:
(3S)-1-Diphenylmethyl-3-hydroxypyrrolidine (4.00 g) was dissolved in methylene chloride (11 mL), and the solution was stirred under cooling with ice. Triethylamine (3.3 mL) was added dropwise to the reaction mixture, and p-toluenesulfonyl chloride (3.61 g) was added to the resultant mixture, followed by stirring at room temperature for 12 hours and then at 40° C. for 4.5 hours. Since the starting materials partially remained unconsumed, triethylamine (1.1 mL) and p-toluenesulfonyl chloride (1.5 g) were added to the reaction mixture and then stirred for 24 hours. The reaction mixture was extracted with water and chloroform, and the organic layer was dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (4.40 g, yield 68.5%). The thus-obtained compound was purified through recrystallization from isopropyl alcohol.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([O:25][CH2:26][CH3:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[Cl:24].[Li+].[OH-]>>[C:20]([C:16]1[O:17][C:18]([CH3:19])=[C:14]([CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:25][CH2:26][CH3:27])[C:3]([OH:28])=[O:2])=[C:7]([Cl:24])[CH:8]=2)[N:15]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1Cl)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1Cl)C(=O)O

Procedure:
In analogy to the procedure described in example 46 d], (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-chloro-phenyl]-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-chloro-phenyl]-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([CH:27]=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1>C(Cl)Cl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:13][C:12]3[C:2]([F:1])=[C:3]([CH:9]=[CH:10][CH:11]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc(S)c1F
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate 6 (2.8 g, 14.0 mmol) in CH2Cl2 (30 mL) under inert atmosphere was added NCS (1.9 g, 14.0 mmol) at RT and allowed to stir for 2 h. To this, compound 5 (3.9 g, 12.8 mmol) in CH2Cl2 (10 mL) was added at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×80 mL). The combined organic extracts were washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by triturating with n-pentane (2×50 mL) to afford 7 (5.2 g, 81%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); MS (ESI): m/z 502.5 (M+H+); HPLC: 97.5%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.
Reaction SMILES: C(O)(=[O:15])CCCCCCCCCCCCC.OO.[CH3:19][C:20]1([CH3:42])[S:24][C@@H:23]2[C@H:25]([NH:28][C:29]([CH2:31][O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[C:26](=[O:27])[N:22]2[C@H:21]1[C:39]([OH:41])=[O:40].[K].P([O-])([O-])([O-])=O>C1(C)C=CC=CC=1.C(#N)C>[CH3:19][C:20]1([CH3:42])[S:24](=[O:15])[C@@H:23]2[C@H:25]([NH:28][C:29]([CH2:31][O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[C:26](=[O:27])[N:22]2[C@H:21]1[C:39]([OH:41])=[O:40]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: OO
Agent: [K]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2S1=O
Reaction time: 5 h

Procedure:
To a mechanically stirred suspension of immobilized C. antarctica lipase (150 mg, according to example 1) in toluene (15 ml) and myristic acid (1 g, 4.6 mmol), was hydrogen peroxide (1.2 ml 60% (w/v), 21 mmol in all) added in four equal portions after 0, 2, 3 and 4 hours. Penicillin V-potassium salt (2.4 g, 6.2 mmol in all) was added in three equal portions after 2, 3 and 4 hours. The yields were determined by HPLC (Column: Supelco RP-18, 5 micro; Mobile phase: Acetonitrile 20% and pH 6.5 Phosphate buffer 80%; Flow: 1 ml/min. UV-detector). Full turnover was reached after 5 hours total reaction time.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[O:17]1[C:22]2[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=2[NH:20][CH2:19][CH2:18]1>>[O:17]1[C:22]2[CH:23]=[C:24]([O:27][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)[CH:25]=[CH:26][C:21]=2[NH:20][CH2:19][CH2:18]1
Reactant: Oc1ccc2c(c1)OCCN2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Yield: 74 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 182 using Compound 83 (250 mg, 1.08 mmol) and 3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (328 mg, 2.17 mmol) to provide 218 (276 mg, 74% yield) as a tan solid. LC-MS (M+H=346, obsd.=346).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2cccnc2c1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (2.20 g, 12.3 mmol) in toluene (300 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (5.88 g, 25.9 mmol) and the reaction was heated to 90° C. for 1.5 h. After cooling to room temperature, the suspension was filtered and the filtrate concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 30% EtOAc in 40-60° C. petroleum ether gave the title compound as a cream solid (1.74 g). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.08 (dd, 1H), 8.98 (d, 1H), 8.30 (dd, 2H), 7.99 (d, 1H), 7.62 (dd, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][NH:12][C:13](=O)[CH3:14])[C:4]=2[O:3][CH2:2]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:14][C:13]1[C:8]2[C:9]([CH2:10][CH2:11][N:12]=1)=[C:4]1[O:3][CH2:2][O:1][C:5]1=[CH:6][CH:7]=2
Reactant: CC(=O)NCCc1cccc2c1OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c1ccc1c2OCO1

Procedure:
In close analogy to the procedure described above, N-(2-Benzo[1,3]dioxol-4-yl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].CO.[BH4-].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(Cl)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: OCc1cc(Cl)ccc1Br
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
2-Bromo-5-chlorobenzaldehyde (20.5 g) from Example 72 was dissolved with dry methanol (200 ml), followed by sodium borohydride (1.06 g) at 0° C., and the mixture was stirred for 30 minutes. After addition of acetone, the solvent was removed under reduced pressure, water was added the obtained residue, and then extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (19.5 g; 94%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[N+:12]([O-])=O.C(=O)([O-])O.[Na+].[H][H]>[C].[Pd].O>[NH2:12][C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: COc1ccnc(C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccnc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
4-Methoxy-3-nitropyridine-2-carboxylic acid (1.35 g, 6.81 mmol), sodium hydrogencarbonate (690 mg, 817 mmol), water (10 mL) and 10% palladium-carbon (135 mg) were stirred in a hydrogen atmosphere at room temperature for 24 hours. The reaction solution was filtered through Celite, the Celite was washed with water and methanol, and the mother liquid was concentrated. 2 N hydrochloric acid was added to the resulting residue, and the solution was controlled to have a pH of 1. The reaction solution was stirred at 0° C. for 1 hour, and the resulting pale gray solid was taken out through filtration and dried to obtain the intended compound (940 mg, 56%).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>ClCCl>[C:25]1([CH3:33])[CH:30]=[CH:29][C:28](/[CH:31]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:27][CH:26]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(C)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
2.0 g of methyl (triphenylphosphoranylidene)acetate and 720 mg of p-toluenealdehyde are dissolved in 10 ml of dichloromethane and stirred at room temperature for twelve hours. Then, 4 g of kieselguhr are added, and the solvent is removed in vacuo. The resulting residue is purified on silica gel with n-heptane:ethyl acetate=4:1 as eluent. 850 mg of methyl trans-3-p-tolylacrylate are obtained as an oil.