Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].N[C@H](C1C=CC=C([N+]([O-])=O)C=1)CC(O)=O.S(Cl)([Cl:36])=O>>[ClH:36].[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C[C@H](N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: N[C@@H](CC(=O)O)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)C[C@@H](N)c1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
Using a procedure analogous to that used to prepare 34A, (S)-3-amino-3-(3-nitrophenyl)propanoic acid (2.1 g, 10 mmol) was reacted with thionyl chloride to 10 afford 39A (2.75 g, 99%) as a white solid. MS (ESI) m/z 239.08 (M+H)+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][CH:48]([CH3:52])[CH:49](O)[CH3:50]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH:49]([CH3:50])[CH:48]([CH3:52])[CH3:47])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: CC(C)C(C)O
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OC(C)C(C)C)cccc2[nH]1
Reaction time: 72 h

Procedure:
DEAD (5.3 ml, 34.1 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (5 g, 24.36 mmol), triphenylphosphine (8.95 g, 34.1 mmol) and 3-Methyl-butan-2-ol (3.58 ml, 33.13 mmol) in 50 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 3 days and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using first cyclohexane as eluent, then increasing amounts of EtOAc (from 5% to 50%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=C(Cl)C=CC=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: C[N+](C)=Cc1ccc(Cl)cc1Cl
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: CN(C)C(c1ccc(Cl)cc1Cl)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2,4-dichloro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2,4-dichloro-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH2:11]([SH:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([S:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCS
Reactant: O=Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.0 g of 4-chloro-2-fluorobenzaldehyde, 2.05 ml of ethanethiol, 3.82 g of potassium carbonate and 6 ml of DMF was stirred at room temperature for 6 hours, and was allowed to stand overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 3.57 g of 4-chloro-2-ethylsulfanylbenzaldehyde. 4-Chloro-2-ethylsulfanylbenzaldehyde
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:35])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:14]=2[CH:34]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:35][S:44]([C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)(=[O:46])=[O:45])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:15]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:14]=2[CH:34]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccc(OC)cc1)n2-c1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccc(OC)cc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-(4-methoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O1CCCC1>C(O)C.[C].[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.5 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (20 g) in ethanol (200 ml)-tetrahydrofuran (125 ml) was added 10% palladium carbon (6.0 g), followed by stirring under a hydrogen atmosphere at room temperature for 4.5 hrs. The mixture was filtered to remove the catalyst, which was washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (16.1 g, 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH:22]([Mg]Br)=[CH2:23].C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]([OH:18])[CH:22]=[CH2:23])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. No. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0° C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0° C., the reaction was quenched by the slow addition of saturated NH4Cl solution (150 ml), followed by H2O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110°-112° C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:38]([CH:34]4[CH2:37][CH2:36][CH2:35]4)=[O:39])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclobutanecarbonyl chloride (0.04 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 69 (37 mg, 30% yield) as a white fluffy solid. LC-MS (M+H=425, obsd.=425).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)\[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(C(F)(F)F)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-3-trifluoromethyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.95 (d, 1H), 7.72 (d, 1H), 7.50-7.63 (m, 3H), 7.36-7.42 (m, 4H), 7.08 (t, 1H), 6.64-6.68 (m, 2H), 6.42 (d, 1H), 4.96 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13].N1C=CC=CC=1>ClCCl>[Br:13][C:8]1[CH:9]=[N:10][N:11]([CH3:12])[C:7]=1[N:6]=[S:2]([CH3:3])[CH3:1]
Reactant: Cn1ncc(Br)c1N
Reactant: CSC
Agent: ClCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1N=S(C)C

Procedure:
A solution of 0.60 mL (8.2 mmol) of dimethyl sulfide in 30 mL of dichloromethane was cooled to -20° C. and 0.50 g (7.0 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 1.0 g (5.7 mmol) of 5-amino-4-bromo-1-methylpyrazole and then 1.0 g (12.7 mmol) of pyridine were added with cooling and stirring. A 2 mL aliquot of this mixture was removed and the light yellow solids present were collected by filtration and washed with deuteroacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:22]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:37])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCCCC3)c2C)c(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(S(=O)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a stirred solution of 5-chloro-3-(cyclohexylthio)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.2 g, 0.48 mmol) in DCM (7 mL) at 0° C., m-CPBA (0.098 g, 0.57 mmol) was added and stirred at 0° C. for 2 h. Reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and washed with aqs. NaHCO3. The product was purified by solvent washings to afford the title compound (0.17 g, 82.3%).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH2:25]C)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:28][NH2:29]>O1CCCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:28][NH2:29])(=[O:3])[NH2:2]
Reactant: NN
Reactant: CCOc1cc(C(=O)OC)ccc1Nc1nc(SC)nc(Cl)c1C(N)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(SC)nc(NN)c2C(N)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of Example 11A (1.2 g, 3.1 mmol) in tetrahydrofuran (400 mL) was added hydrazine hydrate (550 mg, 9.4 mmol) and the mixture was stirred at ambient temperature for 12 hours. After concentration, the residue was washed with methanol and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 379 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:28]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:39][C:36]2[CH:35]=[CH:34][C:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(-c2cccnc2)cc1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(-c2cccnc2)cc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-pyridin-3-ylphenol (J. Med. Chem. 1986, 29, 1461): 1H-NMR (CDCl3) δ 8.88 (1H, m), 8.64–8.53 (2H, m), 8.17 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=7.5 Hz), 7.96 (2H, d, J=8.4 Hz), 7.69 (2H, d, J=8.6 Hz), 7.47 (1H, d, J=8.6 Hz), 7.42 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.6 Hz), 6.97 (1H, d, J=8.6 Hz), 5.38 (1H, m), 1.60 (3H, d, J=7.5 Hz), 1.57 (9H, s).
Reaction SMILES: C(OC(N1CCC([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.N[C@@H:32]([CH2:41][OH:42])[C@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:34]>>[OH:34][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:32]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:41][OH:42]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Product: O=C(N[C@@H](CO)[C@@H](O)c1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (1S,2S)-2-amino-1-phenyl-1,3-propanediol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 409 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (1H, br. s.) 9.67 (1H, s) 7.99 (1H, d, J=5.37 Hz) 7.76 (1H, d, J=5.32 Hz) 7.45 (1H, d, J=8.64 Hz) 7.33 (1H, d, J=5.37 Hz) 7.27 (1H, dd, J=3.54, 2.22 Hz) 7.21-7.25 (2H, m) 7.10-7.21 (3H, m) 6.62 (1H, d, J=5.42 Hz) 6.36 (1H, dd, J=3.54, 1.73 Hz) 5.55 (1H, d, J=4.73 Hz) 4.90 (1H, dd, J=4.83, 3.17 Hz) 4.84 (1H, t, J=5.64 Hz) 4.07 (1H, dt, J=7.80, 5.30 Hz) 3.50 (1H, dt, J=10.58, 6.96 Hz) 3.40 (1H, dt, J=10.55, 5.34 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].BrBr.BrC(C1C=CC(S(C)(=O)=O)=C(F)C=1)C(=O)C.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([NH:42][C:43]([NH2:45])=[S:44])=[CH:38][CH:37]=1>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:44][C:43]([NH:42][C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)=[N:45][C:9]=2[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: COc1ccc(NC(N)=S)cn1
Agent: BrBr
Agent: CC(=O)C(Br)c1ccc(S(C)(=O)=O)c(F)c1
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(Nc2nc(C)c(-c3ccc(Cl)c(S(C)(=O)=O)c3)s2)cn1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(4-chloro-3-methanesulfonyl-phenyl)-propan-2-one (32b) (0.23 g, 1 mmol) is dissolved in dioxan (10 ml) and the solution is cooled to 10° C. at which point the mixture is semi-frozen. Bromine (0.045 ml, 0.8 mmol, 0.8 eq.) is added slowly and the mixture is stirred for an additional 15 minutes in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (10 ml). (6-Methoxy-pyridine-3-yl)-thiourea (0.183 g, 1 mmol) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the product crystallised. Filtration affords the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][CH:13]=2)[CH2:11][CH3:12])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCC(Oc1ccc(Cl)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccc(Cl)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 104.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 730 mg of (2RS)-2-(4-chlorophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.42 g of the title compound as a colorless foam.
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[C:1]12([NH:11][C:21](=[O:22])[CH2:20][Br:19])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Br)CBr
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CBr)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.8 %

Procedure:
To an anhydrous toluene solution (25 ml) at 0° C. containing 1-adamantanamine (4.445 g, 29.39 mmol) and triethylamine (4.92 ml, 35.27 mmol) under a nitrogen atmosphere was added dropwise with strirring a solution of bromoacetyl bromide (2.56 ml, 29.39 mmol in 10 ml of toluene). The solution was warmed to ambient temperature and stirred for 2.5 hours. The triethylamine (TEA) salts were filtered and washed with toluene. The filtrate was extracted with 1 M HCl and brine, dried (Na2SO4) and concentrated in vacuo to yield 5.74 g (71%) of the title compound as a light brown solid which was crystallized from ether/hexane.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10].[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([N:8]=[N+:9]=[N-:10])=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Temperature: 10 °C
Yield: 55.5 %

Procedure:
A solution of thiophene-2-carbaldehyde (650 mg, 5.8 mmol) and ethyl azidoacetate (6.89 grams, 53.4 mmol) in dry toluene (40 ml) was added to a cold (−5° C.) solution of sodium ethoxide (about 53 mmol) in ethanol (60 ml) during a time period of one hour, under nitrogen atmosphere. Stirring was continued for another hour while maintaining the temperature under 10° C. The reaction mixture was then cooled to 0° C. and acidified with HCl 0.1 M. After separation of the phases, the aqueous phase was extracted with ether (3×30 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 718 mg of pure 2-azido-3-thiophen-2-yl-acrylic acid ethyl ester (55% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]=[S:9].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:15][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:9])[CH3:11]
Reactant: S=C=Nc1ccccn1
Reactant: CCOC(CN)OCC
Solvent: CCO
Product: CCOC(CNC(=S)Nc1ccccn1)OCC
Yield: 68.2 %

Procedure:
To a solution of 11.1 g of 2-pyridylisothiocyanate dissolved in 100 ml of ethanol, was added 10.0 g of aminoacetaldehyde diethylacetal, followed by stirring of the resulting mixture under reflux with heating for 40 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. Crystals precipitated were collected by filtration to give 13.8 g of N-2,2-diethoxyethyl-N'-(2-pyridyl)thiourea (m.p.: 132° to 133° C.). To the thus obtained crystals was added 120 ml of 10% diluted hydrochloric acid, followed by stirring of the resulting mixture under reflux with heating for 30 minutes. The reaction mixture was cooled and adjusted to pH of 5 to 6 with use of 50% aqueous sodium hydroxide to precipitate crystals. The crystals precipitated were filtered out, washed with water and dried to give 8.3 g of the desired compound. m.p.: 162° to 163° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.[OH-].[Na+]>C(O)C>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccccc3F)noc2c1Cl

Procedure:
A mixture of 10.0 g of ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, 100 ml of 10% sodium hydroxide, and 350 ml of ethyl alcohol is refluxed for 3.5 hours. Thereafter, the ethyl alcohol is removed under vacuum and the residue is acidified with a 5% hydrochloric acid solution effecting a solid precipitate. The precipitate is collected by filtration and dried. The dried product is recrystallized from 95% ethyl alcohol to yield the product {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 190° to 191° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C>[CH2:1]([NH:8][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
0.28 ml (2.52 mmol) of benzylamine is added to a solution of 150 mg (0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 159 mg (74.4% of theory) of the title compound are obtained and reacted further without further purification. LC-MS (Method 3): Rt=3.83 min.; m/z=369 (M+H)+.