Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:22])[C:18]=2[C:19]([NH2:21])=[O:20])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1csc(N)c1C(N)=O
Product: COc1ccc(CC(=O)Nc2scc(C)c2C(N)=O)cc1

Procedure:
The title compound was prepared from 2-(4-methoxyphenyl)acetic acid (1.21 g, 7.22 mmol) and 2-amino-4-methylthiophene-3-carboxamide (1.12 g, 7.22 mmol) according to protocol B. Retention time (min)=1.903, method [1], MS (ESI) 305.0 (M+H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=2[F:48])[CH2:17][O:16][C@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]1[CH2:39][OH:40]>C(Cl)Cl>[F:48][C:42]1[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:39][OH:40])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:16][CH2:17]1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Yield: 96.7 %

Procedure:
Benzoyl isothiocyanate (1.24 mL, 9.2 mmol) was added to a stirred solution of ((2S,3R,4S)-4-amino-4-(2,4-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol (4.2 g, 8.4 mmol) in dry DCM (20 mL) at RT under nitrogen. After 1 hour the volatiles were removed in vacuo and then the residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (5.4 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.71-2.83 (m, 1 H) 3.12 (dd, J=10.15, 4.52 Hz, 1 H) 3.27 (dd, J=10.15, 3.67 Hz, 1 H) 3.83 (d, J=5.26 Hz, 2 H) 4.19-4.27 (m, 1 H) 4.55 (d, J=9.78 Hz, 1 H) 5.18 (d, J=9.78 Hz, 1 H) 6.82-6.96 (m, 2 H) 7.17-7.32 (m, 9 H) 7.36-7.41 (m, 6 H) 7.49-7.57 (m, 3 H) 7.60-7.67 (m, 1 H) 7.89-7.94 (m, 2 H),
Reaction SMILES: [CH3:1][NH2+:2][CH3:3].[F:4][C:5]([F:15])([F:14])[C:6]1[CH:7]=[C:8]([NH:12][NH2:13])[CH:9]=[CH:10][CH:11]=1.CNC>CCOCC>[F:4][C:5]([F:14])([F:15])[C:6]1[CH:7]=[C:8]([N:12]2[CH:3]=[N:2][CH:1]=[N:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[NH2+]C
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: CNC
Solvent: CCOCC
Product: FC(F)(F)c1cccc(-n2cncn2)c1
Temperature: 60 °C

Procedure:
A mixture of 16.4 g of 2A and 17.6 g of 3-trifluoromethylphenylhydrazine were stirred and heated to 60° C. Dimethylamine was evolved in an exothermic reaction and the temperature maintained at 90° C. until evolution ceased (about 30 minutes). After cooling, the reaction mixture was dissolved in ether, washed with water, dried and chromatographically purified to yield 1-(3-trifluoromethylphenyl)-1,2,4-triazole (2B).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH2:43])=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH:43][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
2-Phenylacetic acid (592 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide (606 mg, 80.1% yield) was obtained as a solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[Na+].[CH3:9][NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:27]([O:65][CH3:66])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:63][CH3:64])[C@@H:37]([CH3:62])[C:38]([NH:40][C@@H:41]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:46]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]([CH3:14])[CH3:13].O=[CH:72][CH2:73][CH2:74][C:75]([OH:77])=[O:76].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:75]([CH2:74][CH2:73][CH2:72][N:10]([CH3:9])[C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:27]([O:65][CH3:66])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:63][CH3:64])[C@@H:37]([CH3:62])[C:38]([NH:40][C@@H:41]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:50]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH:12]([CH3:14])[CH3:13])([OH:77])=[O:76]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: O=C([O-])C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
11.5 mg (12 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-{[4-(methoxycarbonyl)benzyl]oxy}-3-phenylpropane-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide sodium trifluoroacetate (intermediate 46) were dissolved in 0.7 ml of dioxane/water (1:1) and treated in analogy to example 1 with 15 aqueous solution of 4-ketobutyric acid in the presence of sodium cyanoborohydride. Following lyophilization from dioxane, the yield was 8.3 mg (74% o. th.) of the title compound in the form of a white solid substance.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=[O:13].[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].Cl>C1CCN2C(=NCCC2)CC1>[CH3:21][O:20][Si:19]([O:22][CH3:23])([O:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:10]([C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[CH2:11][C:12](=[O:13])[CH3:14]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: CO[Si](CCCS)(OC)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CO[Si](CCCSC(CC(C)=O)C1=C(C)CCCC1(C)C)(OC)OC
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To a well-stirred mixture of β-ionone (10.00 g, 52.1 mmol) and DBU (79 mg, 0.52 mmol (1 mol-%)) was rapidly added 3-mercaptopropyltrimethoxysilane (10.21 g, 52.1 mmol) at 25-30° C. After 72 hours, the reaction mixture was poured onto a cold stirred 5% aqueous HCl solution and extracted twice with Et2O. The organic phases were washed (H2O, saturated aqueous NaHCO3 and brine), dried (Na2SO4), filtered and concentrated. The crude extract was dried for 1 hour at 65-70° C./0.01 Torr to give 18.00 g of the title thioether containing approximativaly 10% of β-ionone. Yield: 80%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: c1cc(C2CCCN2)cs1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccsc1

Procedure:
The title compound, white solid, m.p. 135° C. and MS: m/e=312.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-3-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Formic acid (7 mL, 186 mmol) and acetic anhydride (140.1 mL, 150 mmol) were heated together at 55° C. for 2 hours. The mixture was cooled to room temperature, THF (11 mL) was added followed by 4-bromoaniline (10 g, 58 mmol) in THF (20 mL). The mixture was stirred at room temperature for 3 hours before evaporating to dryness. Trituration of the solid gave the subtitled compound as a light brown solid (8.22 g). MH− 198/200. 1H NMR δ (CDCl3) 6.93-7.04 (2H, d), 7.24 (2H, s), 8.59-8.70 (1H, d).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=O)=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Na+].S(Cl)([Cl:17])=O>CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([Cl:17])(=[O:13])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
A suspension of 100 g. of sodium 4-acetylbenzenesulfonate in 225 ml. of dimethylformamide is treated with 31 ml. of thionyl chloride and the mixture is stirred at room temperature for 5 minutes, then poured into 1 l. of ice water. The resulting precipitate of 4-acetylbenzenesulfonyl chloride is collected by filtration and washed with ice water. The still-damp product may be used as such without further purification. However, if purification is desired, the following procedure may be used: The product is dissolved in methylene chloride and the solution is dried and evaporated at reduced pressure. The residual sulfonyl chloride is crystallized from benzene/hexane; m.p. 83°-85° C.
Reaction SMILES: [Cl:1]Cl.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>CO>[Cl:1][C:5]1[C:4]([OH:3])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc(O)c1
Reactant: ClCl
Solvent: CO
Product: O=C(O)c1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
Chlorine gas (10.3 g; 147 mmol) was slowly bubbled through a cold solution of 20 g (145 mmol) of 3-hydroxy benzoic acid in 100 mL of methanol, under nitrogen, while maintaining the temperature below -60° C. After approximately thirty minutes, the chlorine gas was flushed out with nitrogen and the reaction mixture was allowed to warm to room temperature and diluted with 100 mL of water. The desired titled compound was isolated by recrystallization to provide a white solid. This solid was purified by recrystallization from 50 mL of water followed by recrystallization from 130 mL of benzene containing 10 mL of acetone to provide the desired titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: BrCc1ccccn1
Reactant: O=Cc1ncc[nH]1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1nccn1Cc1ccccn1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a solution of the 2-imidazolecarboxaldehyde (545 mg, 5.67 mmol) and 2-(bromomethyl)pyridine hydrobromide (1.58 g, 6.24 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (3.0 mL, 17.01 mmol). The reaction mixture was heated to 80° C. overnight. Then it was cooled and quenched with saturated NaHCO3 (20 mL). It was extracted with CH2Cl2 (c×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a dark brown oil. Purification by flash column chromatography on silica gel using 1%→2% CH3OH/CH2Cl2 afforded the product as a yellow solid (397 mg, 37%). 1H NMR (CDCl3) δ 5.71 (s, 2H), 7.18-7.24 (m, 2H), 7.32 (s, 1H), 7.36 (s, 1H), 7.65 (td, 1H, J=10.4, 1.5 Hz), 8.56 (d, 1H, J=4.5 Hz), 9.82 (s, 1H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1(C(=O)N)C(CCC2C=CC=CC=2)CCCCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH2:19]([NH:18][C:16](=[O:17])[NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:8]1[C:6]([OH:7])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CCCCC(CCc3ccccc3)C2(C(N)=O)C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)O)cc1

Procedure:
3-(3-Benzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (25 mg, 0.05 mmol) is reacted in the same manner as 1-(4-Methoxybenzenesulfonyl)-3-phenethyl carbamoyl-azepane-2-carboxylic acid tert-butyl ester and purified by flash-chromatography, Dichloromethane/Methanol (9:1): Cal. 458.5 found (M-H)+ 458.2; 1H NMR (DMSO, 400 MHz), ppm: 7.79 (d, 2H), 7.30 (m, 2H),7.20 (m, 3H) 7.02 (d, 2H), 5.60 (m, 1H), 5.50 (m, 1H) 4.3 (m, 3H), 4.00 (m, 1H), 3.93 (m, 3H), 2.81 (t, 2H),2.35 (m, 2H), 2.05 (m, 2H).
Reaction SMILES: [CH:1]([O:3][C:4](Cl)=[O:5])=[CH2:2].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[CH2:9]([O:8][P:7]([C:4]([O:3][CH:1]=[CH2:2])=[O:5])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: C=COC(=O)Cl
Product: C=COC(=O)P(=O)(OCC)OCC
Temperature: 0 °C

Procedure:
2.0 g (19 mmol) of chloroformic acid vinyl ester were precharged into a 50 ml two-necked flask, and, while stirring at 0° C., 3.13 g (19 mmol) of triethyl phosphite were slowly added dropwise. After completion of the addition, the reaction mixture was stirred for further 2 hours at room temperature. For complete removal of the ethyl chloride formed during the reaction, the solution was heated to 40° C. for 30 minutes. Purification by vacuum destillation yielded 2.5 g (64% of th.) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[CH:18]=[C:17]([Cl:19])[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]=1[Cl:20])=O.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[CH:18]=[C:17]([Cl:19])[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]=1[Cl:20])=[N:25][OH:26]
Reactant: NO
Reactant: O=C(c1cccc(Cl)c1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2c(Cl)c(C(=NO)c3cccc(Cl)c3)cc(Cl)c2O1
Yield: 100.3 %

Procedure:
A mixture of 5-(3-chlorobenzoyl)-4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid (11.5 g), hydroxylamine hydrochloride (21.5 g) and pyridine (110 ml) was refluxed for 14 hours. After distilling off the solvent, water was added to the mixture which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water an.d dried. By distilling off the solvent, 12 g of 5-(3-chloro-α-hydroxyiminobenzyl)4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid was obtained. This compound (12 g) was dissolved in anhydrous dimethylformamide (150 ml), and to the ice-cooled solution, 3.9 g of 60% sodium hydride was added in small amounts under agitation. After stirring for 8 hours at room temperature, the mixture was left to stand overnight. After adding water, the mixture was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 5.6 g of 5-chloro- 3-(3-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 168°-169° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 349.
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Na+].[I-:11]>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH2:9][I:11]
Reactant: [I-]
Reactant: COC(=O)CCC(C)Br
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCCCI
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a solution of methyl 4-bromovalerate (14 g) in acetone (63 mL), NaI (11.5 g) was added and the mixture was refluxed for 2 hr. It was then cooled to r.t. and the precipitate was filtered. The filtrate was evaporated and ether was added to the residue. The resulting suspension was filtered and the ethereal phase washed with 5% aq NaHSO3 (3×100 mL) and with brine (1×100 mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to give the crude title compound as a yellow oil (15.85 g).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([C:14]([F:17])([F:16])[F:15])([C:18]([F:19])([F:20])[F:21])[C:11]([O:13][CH3:3])=[O:12])=[CH:22][CH:23]=1
Reactant: O=C(O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
An excess of a solution of diazomethane in ether is added to an ethereal solution of 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid (0.25 g.) at 0° C. Evaporation of the resulting solution yields methyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (0.25 g.), b.p. (bath temperature) 140° C. at 30 mm. pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:23][O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:27](=[O:28])[CH2:26][C:25]([O:24][CH3:23])=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-(4-trifluoromethyl-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonylacetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 7.56 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.0 Hz), 6.84 (d, 1H, J=2.2 Hz), 6.52 (d, 2H, J=2.2 Hz), 5.31 (d, 1H, J=14.6 Hz), 4.48 (d, 1H, J=15.0 Hz), 3.73 (s, 3H), 3.72 (s, 3H), 3.20 (dd, 3H, J=14.6 Hz, 16.2 Hz).
Reaction SMILES: [C:1]([C:3](=[CH:13][C:14]1[CH:19]=[C:18]([O:20]C)[C:17]([OH:22])=[C:16]([Cl:23])[CH:15]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].B(Br)(Br)Br.O>C(Cl)Cl>[C:1]([C:3](=[CH:13][C:14]1[CH:19]=[C:18]([OH:20])[C:17]([OH:22])=[C:16]([Cl:23])[CH:15]=1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: COc1cc(C=C(C#N)C(=O)Nc2ccccc2)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#CC(=Cc1cc(O)c(O)c(Cl)c1)C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a solution of 2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenanilide (340 mg, 1.03 mmol) in methylene chloride (20 ml) chilled at -70° C. was dropwise added 1M solution of boron tribromide in methylene chloride (2.50 ml, 2.5 mmol). The reaction mixture was gradually allowed to warm to room temperature and poured into water. The product was extracted with ethyl acetate, dried over MgSO4 and concentrated. The resulting solid was suspended in diethyl ether, refluxed for 10 minutes and the resultant solid was filtered to give the objective 2-cyano-3-(3-chloro-4, 5-dihydroxyphenyl) propenanilide (260 mg, 80% in yield).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: O=C1CCc2c(OC[C@@H](O)CNC3CCN(c4ccc(CC5SC(=O)NC5=O)cc4)CC3)ccc(O)c2N1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (S)-5-(3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one) (which was obtained in Example 12) according to the procedure of Example 73 as a pale yellowish solid; mp >140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.55 (m, 2H), 1.85-2.00 (m, 2H), 2.40 (t, J=8.0 Hz, 2H), 2.60-3.00 (m, 8H), 3.25 (dd, J=15.9, 3.9 Hz, 1H), 3.50-3.70 (m, 2H), 3.80-4.00 (m, 3H), 4.50 (dd, J=9.7, 3.9 Hz, 1H), 6.34 (d, J=8.9 Hz, 1H), 6.61 (d, J=8.9 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 8.76 (s, 1H), 9.24 (brs, 1H); MS (ES) m/z: 541.1 (MH+); HRMS Calcd. for C27H33N4O6S(MH+): 541.2121. Found: 541.2148.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][S:11][C:10]=2[CH:13]=1)[CH2:26][CH2:25][O:24][CH3:23])[CH3:29]
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Reactant: CCNCCOC
Product: CCN(CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and N-(Methoxyethyl)ethylamine were converted to yield Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-amine as light brown oil, MS: 396 (MH+).