Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]2[CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:3]=12.[Cl:23][C:24]1C(C2C=CC=CC=2C)=CC2CC(C(O)=O)OC=2C=1Cl>>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH3:24])[C:6]=2[CH:5]=[C:4]2[CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:3]=12.[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[Cl:23])[C:6]=2[CH:5]=[C:4]2[CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:3]=12
Reactant: Cc1ccccc1-c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: O=C(O)C1Cc2cc3c(-c4ccccc4)noc3c(Cl)c2O1
Product: Cc1ccccc1-c1noc2c(Cl)c3c(cc12)CC(C(=O)O)O3
Product: O=C(O)C1Cc2cc3c(-c4ccccc4Cl)noc3c(Cl)c2O1

Procedure:
8-Chloro-5,6-dihydro-3-(o-tolyl)furo[3,2-f]-1,2-benzisoxazole-6-carboxylic acid (4e) was prepared in a fashion analogous to (4a) from (3e). A tenacious impurity resulted in the need for esterification, chromatography, and hydrolysis as with (4d). Trituration in n-hexane produced (4e) in 9.4% yield, m.p. 179°-181° C. Analysis (C17H12ClNO4) C,H,N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].ClC1C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
After adding 3-fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml) to ethyl 4-chloropyridine-2-carboxylate (19.4 g), the mixture was heated and stirred for 4 hours at 120° C. under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature. Ethyl acetate (400 ml) and saturated aqueous sodium carbonate (400 ml) were added thereto and the mixture was stirred for 27 hours at room temperature. The stirring was paused and the aqueous layer was separated. Saturated aqueous sodium carbonate was again added to the organic layer, and the mixture was stirred at room temperature for 2 days. The stirring was again paused and the aqueous layer was separated. The aqueous layer was then extracted with ethyl acetate (300 ml). The organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1 to 1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the title compound (12.9 g, 40.2%) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=3)[C:9](=[O:25])[C:8]=2[C:7]([O:26][CH2:27][CH3:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[C:9](=[O:25])[C:8]=2[C:7]([O:26][CH2:27][CH3:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Ethyl [4-(4,9diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (5.86 g, 13.5 mmol) and potassium carbonate (12 g) were added td a mixture of ethanol (146 ml) and water (70 ml) and heated to reflux for 2 h. The solution was cooled to room temperature and the solvent evaporated under vacuum to leave an off-white solid. The solid was slurried in water and the water was evaporated under vacuum. The residue was stirred in hydrochloric acid (2N) for 2 h, filtered and washed with water. Drying of the solid at 40° C. in a vacuum oven gave the title compound as a white solid (4.5 g, 82%)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+]>CO.COC(OC)OC>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 ( 5.20 g, 24.4 mmol) in 50 mL of dry methanol and 50 mL of trimethylorthoformate was added aniline (2.50 g, 1.1 eq.), and the mixture was stirred at room temperature for 30 minutes. NaBH3CN (95%, 1.84 g, 1.1 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 30 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate (1:1) to afford N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 as white solid (5.60 g, 79%). IR (film, cm−1) 3520, 3263, 3004, 2976, 2932, 2854, 1688, 1589, 1521, 1482, 1422, 1365, 1267, 1243, 1175, 1150, 794, 709; 1H NMR (CDCl3, ppm) 7.20 (t, 2H, J=7.8 Hz), 6.72 (t, 1H, J=6.8 Hz), 6.63 (d, 2H, J=8.3 Hz), 4.00–3.78 (m, 3H), 3.07–2.70 (m, 4H), 2.00–1.20 (m, 5H), 1.48 (s, overlap, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Yield: 95.2 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.00 g of 5-{4-(5-benzyloxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 95) was treated with 12 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.63 g of the title compound, melting at 210°-211° C.
Reaction SMILES: [C:1]1([C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:14]([O:18][C:19]([NH:21][C@H:22]([CH:27]=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>O1CCCC1.BrCCBr.CCOCC>[OH:28][C@@H:27]([CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:10]([CH3:12])[CH3:11])[C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@H](CBr)c1ccccc1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](c1ccccc1)C(C)C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
A solution of 40.9 g (0.18 mol) of (S)-(-)-2-phenyl-3-methylbromobutane in 110 ml of tetrahydrofuran and 0.5 ml of 1,2-dibromoethane was slowly added dropwise to a suspension of 6.6 g of magnesium in 25 ml of ether. The temperature rose to 50°. Thereafter, the reaction mixture was stirred at 50° for a further 2 hours and then cooled to -50°. Then, a solution of 13 g (0.06 mol) of N-t-butoxycarbonyl-L-leucinal in 40 ml of tetrahydrofuran was added slowly. After 16 hours at room temperature, the reaction mixture was treated with 200 ml of a 20% ammonium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue (24.3 g) was chromatographed on silica gel with a 4:1 mixture of hexane and ether, to obtain 9.3 g of t-butyl [(1S,2S,4S)-2-hydroxy-1-isobutyl-5 -methyl-4-phenylhexyl]carbamate which has a melting point of 95°-96° after crystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCC>C1(C)C=CC=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.45 g, 0.76 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.25 g, 0.84 mmol), tetrakis(triphenyl-phosphine)palladium (0.053 g, 0.046 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:18](=[O:20])[CH3:19])[CH2:11][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CNc1ccccc1CO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1Cc2cc(Cl)ccc2OCc2ccccc21
Temperature: 80 °C
Yield: 55 %

Procedure:
To a stirred solution of 2-Chloro-11,12-dihydro-6H-5-oxa-11-aza-dibenzo[a,e]cyclooctene Example 348C (43 mg, 0.18 mmol) and DMAP (4.27 mg, 34.9 μmol) in toluene (1.25 mL) was added acetic anhydride (36.0 μL, 0.39 mmol) and pyridine (13.9 mg, 0.18 mmol). This reaction mixture was heated at 80° C. for 50 min, cooled to room temperature and concentrated in vacuo. This was purified by a Shimadzu auto prep HPLC, employing 20% to 100% 10 min gradient elution with 0.1% TFA in MeOH-water solvent system, 220 nM detection, 20 mL/min elution with a YMC ODS S5 20×100 mm column to give 27.7 mg of desired 1-(2-Chloro-6H,12H-5-oxa-11-aza-dibenzo[a,e]cycloocten-11-yl)-ethanone Example 348D in 55% yield. HPLC Rt=3.09 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=288
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[ClH:12].[NH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH3:20]>C(O)(=O)C>[ClH:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH2:19][CH3:20])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1nccn1N
Agent: Cl
Solvent: CC(=O)O
Product: CCc1nccn1N=Cc1ccc(N(C)C)cc1
Reaction time: 24 h

Procedure:
2.24 g (15 mmol) of p-dimethylaminobenzaldehyde are added to a solution of 2.22 g (15 mmol) of 1-amino-2-ethylimidazole hydrochloride in 40 ml of glacial acetic acid. After leaving to stand at room temperature for 24 hours the product is crystallized out by the addition of ether and subsequently recrystallized from ethanol/ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazole hydrochloride of melting point 226°-228°.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[I-].[C:34]1([Zn+])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: [Zn+]c1ccccc1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-1-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and phenylzinc iodide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column and eluted with hexanes:ethyl acetate (3:1) to yield Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (15 mg, 63% yield) as a clear oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3ccsc3)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 80 °C

Procedure:
5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (0.35 g, Example 1c)), thiophene-3-boronic acid (0.053 g), barium hydroxide octahydrate (0.15 g) and tetrakis(triphenylphosphine)palladium (0) (0.0097 g) in ethylene glycol dimethyl ether (6 ml) and water (1 ml) were combined in a sealed vial and stirred with heating at 80° C. for 18 hours. After cooling, the reaction mixture was absorbed onto silica and purified by flash silica chromatography eluting with 25% ethyl acetate in isohexane to give an oil. The oil was triturated with isohexane, filtered and dried under vacuum to give the title compound as a beige solid (0.020 g).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26]>CC#N>[Br-:20].[CH2:28]([NH:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCNC(=O)CCCCBr
Solvent: CC#N
Product: CCNC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.3 %

Procedure:
Triphenylphosphine (2.88 g, 11 mmol, 1.1 eq.) was added to a solution of 5-bromo-N-ethylpentanamide 95 (2.08 g, 10 mmol, 1 eq.) in MeCN (5 ml) and the mixture was stirred for 14 h at 80° C. The mixture was allowed to cool to r.t. and concentrated under vacuum. The residue was added dropwise into Et2O (100 ml) and stirred vigorously for 10 min. The resulting solid was filtered, washed with Et2O (2×10 ml) and dissolved in CH2Cl2 (15 ml). This solution was then added dropwise into Et2O (200 ml) and stirred for 10 min. Solids were filtered, washed with Et2O (2×10 ml) and dried under high vacuum to give the title product 96 as a white powder (3.87 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:20][CH2:21][CH2:22][OH:23]>O.C1(C)C=CC=CC=1>[OH:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(OCCCO)cc1
Temperature: 84 °C

Procedure:
To a flask was added 4-hydroxybenzonitrile (10 g, 82.7 mmol, 1 eq.) and potassium carbonate (13.60 g, 98.7 mmol, 1.25 eq.). To this mixture was added acetonitrile (80 mL) and then, under stirring, 3-bromo-1-propanol (12.25 g, 86.40 mmol, 1.05 eq.). The reaction mixture was heated at reflux (84° C.) for 5 hours before being allowed to cool to room temperature. Toluene (80 mL) and water (50 mL) were added and the resulting mixture was heated (≈30° C.) until all of the solids had gone into solution. The aqueous layer was separated from the organic layer. The organic layer was retained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:16][NH2:17].[OH-].[K+].Cl>>[CH3:16][NH:17][S:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Reactant: CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CNS(=O)(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
6-Bromonaphthalene-2-sulfonyl chloride (576 mg) was added portionwise to 40% methylamine solution (5 ml, WAKO), added with 3.6 N aqueous potassium hydroxide (5 ml), stirred at room temperature, then heated to 60° C. and further stirred for 3 hours. The reaction mixture was cooled to room temperature, then added with 2 N hydrochloric acid (15 ml) and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (Intermediate 30, 484 mg).
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9](Cl)[C:10](Cl)=[C:11](Cl)[C:12]=1Cl)[C:6]([OH:8])=[O:7].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.[C:27](=[O:30])([O-])[O-].[K+].[K+].Cl>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([S:26][C:23]2[CH:24]=[CH:25][C:20]([O:30][CH3:27])=[CH:21][CH:22]=2)[C:10]([S:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[C:11]([S:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:12]=1[S:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:6]([OH:8])=[O:7]
Reactant: CN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: COc1ccc(S)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CN=C(O)c1c(Sc2ccc(OC)cc2)c(Sc2ccc(OC)cc2)c(Sc2ccc(OC)cc2)c(Sc2ccc(OC)cc2)c1C(=O)O

Procedure:
2 g (6.7 millimols) of tetrachlorophthalic acid N-methylimide, 4.23 g (30.15 millimols) of p-methoxythiophenol, 6.25 g (45.2 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 25° C. for 4 hours. The mixture is acidified with 2N HCl solution and extracted with methylene chloride. The extracts are dried over sodium sulfate and evaporated. After recrystallisation from toluene/cyclohexane, 4.68 g (98% of theory) of the title compound are obtained: melting point 168°-70° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(#N)C.O>CO.O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][CH2:28]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: O=C(O)CN1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Yield: 84.8 %

Procedure:
A mixture of compound 347 (50 mg, 97 μmol) and lithium hydroxide, monohydrate (14 μl, 486 μmol) in methanol (9 mL) and water (3 mL) was heated at reflux for 2 h. After cooling, the crude mixture was subjected to reverse phase preparative HPLC (acetonitrile/H2O containing 0.1% TFA each, 40 min from 10 to 40%). Lyophilization provided compound 349 (40 mg) as a light yellow solid (TFA salt). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (1 H, s), 9.62 (1 H, s), 9.38 (1 H, s), 8.68 (1 H, d, J=5.9 Hz), 8.58 (1 H, d, J=6.3 Hz), 8.26-8.48 (2 H, m), 7.89-8.01 (1 H, m), 5.40 (1 H, quin, J=8.9 Hz), 2.75-4.63 (12 H, m), 2.39-2.47 (2 H, m), 2.01-2.23 (4 H, m), 1.70-1.87 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 487.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][N:15]([C:33](=[O:35])[CH3:34])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.5 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (90 mg, 0.22 mmol) obtained in Example 260 and triethylamine (0.092 ml, 0.66 mmol) were dissolved in dichloromethane (4 ml), followed by the addition of acetyl chloride (0.024 ml, 0.34 mmol) at room temperature. After stirring at room temperature for 14 hours, a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added. The residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give a white solid. The solid thus obtained was washed with hexane, whereby the title compound (48 mg, 0.12 mmol, 53%) was obtained as a white powder.