Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:15]Br.O>FC(F)(F)C(O)=O.C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([Br:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCCC2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Br)c2c1CCCC2
Reaction time: 0.25 h

Procedure:
To a mixture of 1-acetylamino-5,6,7,8-tetrahydronaphthalene (1.9 g, 10 mmol) in trifluoroacetic acid (20 ml) was added: bromine (0.55 ml, 10 mmol) solved in acetic acid (5 ml). The mixture was stirred for 15 min at room-temperature. Water (50 ml) was added and the crystals were filtered. Yield 2.6 g (97%). Mp=185.2-188.6° C.
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([OH:23])=O)[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)=[C:5]([CH3:19])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1>CN(C=O)C.O>[CH2:47]([N:57]1[CH2:62][CH2:61][N:60]([C:21](=[O:23])[CH2:20][N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=3)=[C:5]([CH3:19])[CH:4]=2)[CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: Cc1cc(N(C)CC(=O)O)ccc1Oc1ccc([N+](=O)[O-])cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane:methanol=100:1), to thereby yield 1.2 g of the title compound.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([S:14][C:15]#N)=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].[CH2:17](Br)C.[I-].[K+]>CO>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH3:17])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(SC#N)ccc1N
Reactant: CCBr
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccc(N)c(C(=O)O)c1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 31.7 %

Procedure:
To a 500 ml flask fitted with a magnetic stirrer, dropping funnel and thermometer, and containing a solution of 12.7 g (0.192 mol) of 85% potassium hydroxide in 300 ml of methanol was added in portions 10.0 g (0.0481 mol) of methyl 2-amino-5-thiocyanatobenzoate. The solution was cooled to 10° C. and a solution of 6.29 g (0.058 mol) ethylbromide in 50 ml of methanol was added over 10 minutes. This was followed by the addition of 8.0 g (0.048 mol) potassium iodide. After 2.5 hours, the reaction mixture was evaporated to a semi-solid under reduced pressure and treated with 300 ml of water. The aqueous solution was extracted with chloroform, and the organic layer dried over magnesium sulfate. The solution was filtered and evaporated to give 7.5 g (79%) of crude product. This material was recrystallized from hexane to give 3.01 g (32%) of the title compound, m.p. 97°-100° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]1[NH:18][CH2:17][CH2:16][N:15]2[CH2:19][CH2:20][CH2:21][CH:14]12.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]3[CH2:19][CH2:20][CH2:21][CH:14]3[CH2:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CC2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CCN3CCCC3C2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (342 mg, 2 mmol), octahydropyrrolo[1,2-a]pyrazine (252 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol) in dimethylacetamide (10 mL) was heated at 100° C. for 16 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS: 278 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23](B(O)O)([CH3:25])=[CH2:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([C:23]([CH3:25])=[CH2:24])[N:7]=1
Reactant: C=C(C)B(O)O
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester, isopropenylboronic acid, tetrakis(triphenylphosphine)palladium(O) and sodium carbonate in dioxane/water. EI-MS m/e (%): 226 (M+, 74), 225 ([M—H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:32][CH2:33][S:34][C:35](Cl)=[O:36]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[O:22][C:35]([S:34][CH2:33][CH3:32])=[O:36])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reactant: CCSC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
5-Hydroxy-1-methylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (290 mg, 0.82 mmol) was dissolved in dry tetrahydrofuran (15 mL), and triethylamine (166 mg, 1.64 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (107 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an amorphous solid (202 mg, 0.46 mmol) (yield: 56%).
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:24]([C:26]1[C:31]2[N:32]([CH2:35][C:36](O)=[O:37])[CH:33]=[N:34][C:30]=2[CH:29]=[CH:28][CH:27]=1)#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH:23][C:36](=[O:37])[CH2:35][N:32]2[C:31]3[C:26]([C:24]#[N:25])=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]=[CH:33]2)[CH3:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(N)c1ccc(C(C)(C)C)nc1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C(C)(C)C)nc1

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butylpyridin-3-yl)ethyl]amine (intermediate 25) (93 mg, 0.52 mmol), 7-cyanobenzimidazole-1-acetic acid (100 mg, 0.5 mmol), HATU (198 mg, 0.52 mmol) and DIPEA (226 μL, 1.3 mmol). Water is added and the reaction is concentrated then purified by reverse phase chromatography. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.26 (s, 9 H), 1.39 (d, J=7.03 Hz, 3 H), 4.87-4.97 (m, 1 H), 5.12-5.27 (m, 2 H), 7.32 (dd, J=8.01, 7.62 Hz, 1 H), 7.35 (d, J=8.20 Hz, 1 H), 7.66 (dd, J=8.30, 2.25 Hz, 1 H), 7.69 (dd, J=7.52, 0.88 Hz, 1 H), 7.99 (dd, J=8.20, 0.98 Hz, 1 H), 8.32 (s, 1H), 8.45 (d, J=2.54 Hz, 1 H), 8.85 (d, J=7.42 Hz, 1 H). MS [MH+] calc. 362.1981 found 362.3.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[S:32]1[CH:36]=[CH:35][C:34]2[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40][C:33]1=2>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:32]1[CH:36]=[CH:35][C:34]2[CH:37]=[C:38]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:39]=[CH:40][C:33]1=2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3sccc3c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2sccc2c1
Yield: 45.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 2-(benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.131 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.047 g (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C.O.OC1C2N=NNC=2C=CC=1.C(Cl)CCl.O[NH:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][N:45]=[CH:44]2)=[NH:40]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:38]=[C:39]([C:41]3[CH:42]=[C:43]4[C:47](=[CH:48][CH:49]=3)[NH:46][N:45]=[CH:44]4)[N:40]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Temperature: 50 °C
Reaction time: 96 h
Yield: 57.8 %

Procedure:
A mixture of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D31) (350 mg, 1.623 mmol), triethylamine (328 mg, 452 μl, 3.25 mmol), hydroxybenzotriazole hydrate (298 mg, 1.95 mmol), EDC (373 mg, 1.95 mmol) and N-hydroxy-1H-indazole-5-carboximidamide (D2) (430 mg, 2.43 mmol) in DMF (5 ml) was stirred at 50° C. for 4 days. The reaction mixture was cooled to room temperature and diluted with EtOAc (25 ml). The organic layer was washed with a saturated NaHCO3 aqueous solution, water then brine. The organic phase was dried and concentrated in vacuo to give the title compound (334 mg, 58%) as a light red solid which was used in next step without further purification. MS (ES) C17H14ClN5O2 requires 355, found 356 [M+H]+
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH2:1]([O:5][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCCCCBr
Reactant: CCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)CCCCCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled, stirred solution of 39 g (0.52 mol) of butanol and 42 g (0.52 mol) of pyridine in 550 mL of ether was added dropwise 100 g (0.47 mol) of 6-bromohexanoylchloride. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was washed with water, 5% NaHCO3, and again with water. The organic layer was dried (MgSO4), the solvent was removed by rotary evaporation, and the residue was distilled at reduced pressure, bp 120°-125° C. (0.1 mm). A colorless oil was obtained, mass 111 g (94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CCOCC>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Yield: 120.9 %

Procedure:
72.8 g of 2-(4-methylbenzenesulfonylamino)-5-methoxynitrobenzene, prepared in A), are added to 56.5 ml of 4 N sodium hydroxide solution and 29.2 g of 4-chlorobenzyl chloride. The mixture is refluxed for 4 hours, a further 43.7 g of 4-chlorobenzyl chloride are then added and the resulting mixture is refluxed for another 45 minutes. After cooling, 12.2 ml of 35% sodium hydroxide solution are added to the reaction mixture, the latter is refluxed for three hours 45 minutes and then cooled and water and ether are added. The insoluble material is filtered off and washed with water and ether to give 98 g of N-(4-chlorobenzyl)-N-(4-methylbenzenesulfonyl)-2-nitro-4-methoxyaniline in the form of crystals melting at 124° C. Evaporation of the ether phase yields an additional 10 g of crystals melting at 124° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][C:15]([OH:17])=O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.Cl.[CH3:42][O:43][C:44](=[O:49])[C@H:45]([CH2:47][OH:48])[NH2:46].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][C:44](=[O:49])[CH:45]([NH:46][C:15](=[O:17])[CH2:14][C:12]1[S:13][C:9]([C:4]2([CH3:3])[O:5][CH2:6][CH2:7][O:8]2)=[CH:10][CH:11]=1)[CH2:47][OH:48]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC1(c2ccc(CC(=O)O)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C(CO)NC(=O)Cc1ccc(C2(C)OCCO2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-acetic acid (1.25 g, 5.48 mmol) in CH2Cl2 (20 mL) was treated sequentially with DMAP (135 mg, 1.10 mmol), HOBT (1.07 g, 6.80 mmol), EDC (2.68 g, 13.69 mmol) and DIPEA (3.85 mL, 21.9 mmol). After stirring for 1 h at rt, serine methylester hydrochloride (913 g, 5.75 mmol was added and the reaction mixture stirred for 1 h at rt. Sat. aq. NH4Cl was added and the mixture was extracted twice with CH2Cl2. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1000:25:2 CH2Cl2-MeOH—NH4OH) gave the title compound as an orange oil. TLC: rf (EA)=0.3. LC-MS-conditions 01: tR=0.68 min; [M+H]+=329.94.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])O.[Na+].C1C(=O)N(Br)C(=O)C1>CC1(C)N([O])C(C)(C)CCC1.ClCCCl>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CCCCCCC(C)=O
Yield: 95.2 %

Procedure:
2-Octanol (2.0 g, 15.4 mmol), sodium hydrogencarbonate (1.6 g, 18.5 mmol), TEMPO (24 mg, 0.15 mmol) and 1,2-dichloroethane (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice water bath, and thereto was added NBS (3.0 g, 16.9 mmol) divided in two portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give 2-octanone (1.88 g, yield 95%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]1.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])/[C:13](=[CH:23]/[C:22]2[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=2)/[C:12]([CH3:16])=[N:11]1
Reactant: CC1=NN(c2nc3ccccc3s2)C(=O)C1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1=NN(c2nc3ccccc3s2)C(=O)/C1=C/c1ccc(N(C)C)cc1

Procedure:
1 g (4.32 mmol) of 2-(1,3-benzothiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one and 1.93 g (12.96 mmol) of 4-(dimethylamino)benzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and the bright red precipitate is filtered off, then washed with water and a small amount of cold methanol and dried under reduced pressure.
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[C:28]([F:34])[CH:27]=1.Br[C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C@@H:45]2[CH:50]3[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]3)[CH2:46]2)=[O:44])=[CH:38][CH:37]=1.[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43]([C@@H:45]3[CH:50]4[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]4)[CH2:46]3)=[O:44])=[CH:38][CH:37]=2)=[CH:27][C:28]=1[F:34]
Reactant: O=C(Nc1ccc(Br)cc1)[C@H]1CN2CCC1CC2
Reactant: OCc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(CO)c(F)c2)cc1)[C@H]1CN2CCC1CC2
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
492 mg (1.62) of bis(pinacolato)diboron, 804 mg (5.82 mmol) of dry potassium carbonate, and 398 mg (1.94 mmol) of (4-bromo-2-fluorophenyl)methanol are dissolved in 4.2 ml of DMF. Argon is passed through the reaction mixture for 15 minutes, and then 59 mg (0.08 mmol) of PdCl2(dppf) are added, and the mixture is heated at 85° C. overnight. Then, 500 mg (1.62 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 8.1 ml of 1N sodium hydroxide solution and a further 59 mg (0.02 mmol) of PdCl2(dppf) are added. The mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC. 21 mg (3% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]#[C:6][C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:2].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].CO.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:21][O:20][C:16]([C:17]1[S:18][C:5]([CH:4]([O:13][CH2:14][CH3:15])[O:3][CH2:1][CH3:2])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])=[O:19]
Reactant: COC(=O)CS
Reactant: CCOC(C#CC(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(C(F)(F)F)c(C(=O)OC)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A solution of 5,5-Diethoxy-1,1,1-trifluoro-pent-3-yn-2-one (2.16 g, 9.64 mmol) in THF (30 ml) was cooled to 0° C. (ice bath). Methyl thioglycolate (0.88 ml, 9.64 mmol) was added in one portion and the mixture was stirred at 0° C. for 1.5 h. Methanol (6 ml) and Cs2CO3/MgSO4 (2 g/4 g, pre-dried at 200° C. in vacuum) were added at 0° C. The mixture was stirred at 0° C. for 15 min and then at rt for 15 h. The reaction mixture was quenched by pouting into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-30% EtOAc in hexane to afford the desired product (1.90 g, 63% yield).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C>[NH2:8][C@H:12]([CH2:11][OH:10])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)COC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)CCc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 83.8 %

Procedure:
To a solution of (S)-4-{2-[4-(4-chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (438 mg) in acetonitrile (5 ml) were added water (4 ml) and trifluoroacetic acid (0.29 ml). The mixture was heated at 80° C. for 4.5 h. The mixture was then cooled to room temperature and poured into 1 M aq. NaOH and extracted twice with EtOAc/THF. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford N-[4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-4-chloro-benzamide (255 mg, 84%) a white solid. MS (ISP): 321.2 ([{37Cl}M+H]+), 319.2 ([{35Cl}M+H]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)C1C=CC=CC=1.C[N+]1([O-])CCOCC1>ClCCl.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH:26]=[O:27])(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1cccc(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: O=Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1cccc(S(=O)(=O)c2ccc(CCc3ccc(F)cc3F)cc2)c1
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of [3-({4-[2-(2,4-difluorophenyl)ethyl]phenyl]sulfonyl)phenyl]methanol (prepared from 3-({4-[E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde (Example 50 Step 1) according to the method of Example 117) in dichloromethane (4 mL) was added 4 Å molecular sieves (0.1 g) and the mixture stirred for 10 minutes. 4-Methylmorpholine N-oxide (68 mg, 0.58 mmol) was added in one portion and the reaction stirred for 10 minutes, then tetrapropylammonium perruthenate (6.9 mg, 0.02 mmol) added. The reaction was stirred for 30 minutes then diluted with ethyl acetate, filtered through a pad of silica and washed with further ethyl acetate. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to yield 3-({4-[2-(2,4-difluorophenyl)ethyl]phenyl)sulfonyl)benzaldehyde (103 mg, 68%). δH (400 MHz, CDCl3): 10.06 (1H, s), 8.40 (1H, s), 8.18 (1H, d, J=7.8 Hz), 8.07 (1H, d, J=7.6 Hz), 7.87 (2H, d, J=8.3 Hz), 7.69 (1H, t, J=7.7 Hz), 7.30 (2H, d, J=8.2 Hz), 6.99 (1H, q, J=7.9 Hz), 6.79-6.73 (2H, m), 2.95-2.87 (4H, m). m/z (ES+) 387 [MH+].