Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[NH:16][C:15]1[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:14]=1[F:13]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 82 %

Procedure:
25 g 1,3,5-trifluoro-2-nitrobenzene (141.2 mmol, 1 eq.) and 33.5 g 2-fluoro-4-iodoaniline (141.2 mmol. 1 eq.) were dissolved in 250 mL dry THF and cooled with ice-salt to −10 to 0° C. upon which 424 mL lithium hexamethyldisilazide (LiHMDS) solution (1M in THF; 424 mmol, 3. eq.) were added slowly over a 1 h periode. Upon completion of addition of base, the reaction mixtures was allowed to warm to rt and stirring was continued for 5 days. The reaction mixture was quenched with 0.5 N hydrochloric acid and diluted with ethyl acetate. Saturated ammonium chloride solution was added to facilitate phase separation. The separated aqueous phase was reextracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give dark solid residue. The residue was purified by flash column chromatography on silica gel with hexane and hexane/ethyl acetate 8:2 as eluent to yield 45.8 gram (82% yield) of the analytically pure target compound as a slightly brownish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.Cl.O([NH2:20])C.O.[OH-].[Na+]>N1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: CON
Reactant: O=C(Cc1ccncc1)c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(Cc1ccncc1)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(pyridin-4-yl)ethanone (22) (2.0 g, 8.7 mmol) in pyridine (24 mL) was added methoxyl amine hydrochloride (1.45 g, 17.4 mmol) in one portion at room temperature. The resulting mixture was stirred at 50° C. for one hour. The pyridine was removed under vacuum, and residue was added water and extracted with ethyl acetate. Ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave a mixture of geometrical oxime isomers (1.77 g, 78%) as a yellow oil. To a solution of above mixture of syn- and anti-oximes, (1.77 g, 6.8 mmol) in THF (32 mL) at room temperature was added borane-THF complex (1M, 17 mL). The resulting solution was refluxed for 3 hours, and cooled to 0° C. Water (28 mL) was carefully added followed by 20% NaOH (28 mL). The resulting biphasic mixture was refluxed overnight, and allowed to cool to room temperature. The mixture was extracted with ethyl acetate. Combined ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated to give 1-(2-chlorophenyl)-2-(pyridin-4-yl)ethanamine (23) (1.2 g 76%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[C:12]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:14])=[O:13].[C:35]1(C)C=CC=C[CH:36]=1>>[CH2:35]([O:14][C:12](=[O:13])[CH2:15][C:7]1[C:6]2[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1)[CH3:36]
Reactant: O=C1COc2ccc(F)cc21
Reactant: Cc1ccccc1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1coc2ccc(F)cc12

Procedure:
A mixture of 5-fluoro-benzofuran-3 (2H)-one (1.52 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(5-fluoro-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.8 g (80%); 223 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:52])[C@@H:5]([O:49][CH2:50][CH3:51])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26]/[CH:27]=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][C:32]=3[Br:47])=[CH:21][CH:20]=2)=[C:9]([Br:48])[CH:8]=1)[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[Br:47][C:32]1[CH:33]=[C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([OH:41])=[O:40])[CH:35]=[CH:36][C:31]=1[O:30][CH2:29]/[CH:28]=[CH:27]/[C:26]#[C:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([O:49][CH2:50][CH3:51])[C:4]([O:3][CH2:1][CH3:2])=[O:52])=[CH:8][C:9]=2[Br:48])=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3Br)cc2)c(Br)c1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3Br)cc2)c(Br)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of (E)(E)(S)(S) 3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester (example 19) (250 mg 0.30 mmol) in THF (2 mL) and ethanol (3 mL) was added 1N sodium hydroxide (3 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with ethyl acetate (×3) and the combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo to give 230 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+]>CN(C=O)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[CH2:9][O:14][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: BrCc1c(Br)cccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 105 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To the solution of 1,3-dibromo-2-bromomethylbenzene (71.3 g) in DMF (300 mL) was added sodium acetate (91.7 g) and the resulting mixture was stirred at 105° C. for 6 h. The mixture was cooled and quenched with water (1500 mL) and extracted with ethyl acetate (1000 mL×2). The combined organic layers were washed with water (1000 mL) and brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column (200-300 mesh, eluting with petroleum ether/ethyl acetate 30/1) to give acetic acid 2,6-dibromobenzyl ester as a yellow oil (59.42 g, yield 89%). 1H NMR (300 MHz, d6-DMSO) δ 7.57 (d, J=8.0 Hz, 2H), 7.07 (t, J=7.8 Hz, 1H), 5.41 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:18](=[O:21])[NH:19][N:20]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15](O)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].Cl.[CH3:23][NH:24][O:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:26][O:25][N:24]([CH3:23])[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:18](=[O:21])[NH:19][N:20]=[C:6]1[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:14]2)=[O:16]
Reactant: CC(C)Nc1nc2cc(C(=O)O)ccc2n2c(=O)[nH]nc12
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc2c(c1)nc(NC(C)C)c1n[nH]c(=O)n12
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A mixture of 4-isopropylamino-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid (130 mg), N,O-dimethylhydroxylamine hydrochloride (39 mg), HOBT (54 mg), and EDC (77 mg) in DMF (4.0 mL) was stirred at 23° C. for 20 hrs. The solution was then diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions. The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated to afford the title compound as a light yellow solid. MS (M+H)+=331.6.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[CH:10][C:9]=1[CH2:17][C:18]([O:20]C)=O)=O.O.[NH2:23][NH2:24].C(O)(=O)C>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[CH2:17][C:18](=[O:20])[NH:24][N:23]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccco1)OCO2
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2cc3c(cc2C(c2ccco2)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 2-(2-furoyl)-4,5-methylenedioxyphenylacetate (120 mg, 0.42 mmol), hydrazine hydrate (70 μL, 1.2 mmol), and acetic acid (50 μL) in ethanol (20 mL) as a light yellow solid (37 mg, 33%), mp: 234°-236° C. 1H NMR (CDCl3) 8.50 (s, 1H), 7.60 (m, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 6.71 (m, 1H), 6.54 (m, 1H), 6.06 (s, 2H), 3.44 (s, 2H). Anal. Calcd. for C14H10N2O4 : C, 62.22; H, 3.73; N, 10.37. Found: C, 62.07; H, 3.63; N,10.11.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:3]=1[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
[(2-bromo-5-methoxybenzyl)oxy](triisopropyl)silane (1 eq.) was dissolved in anhydrous THF (0.43M solution) and the solution was cooled to −78° C. A solution of n-BuLi (1.6M in hexanes, 1.05 eq.) was added and the resulting mixture was left stirring for 1 h at −78° C. Then triisopropyl borate (50% in THF, 1.3 eq.) was added dropwise and the mixture was allowed to warm to RT overnight. 1N HCl was added and the resulting mixture was left stirring at RT for 30 min. THF was removed in vacuo and replaced with Et2O. The organic phase was washed with water and with brine, then dried over Na2SO4 and evaporated in vacuo. The product was obtained as a colorless oil (64% yield, 65% pure) which was used without further purification in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[O:7]
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(C=O)ccc1OCc1ccccc1
Yield: 92.6 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100.0 g, 0.657 mole), benzyl bromide (112.4 g, 0.657 mole), and potassium carbonate (90.8 g, 0.657 mole) was heated overnight at reflux in 600 ml of dry acetonitrile (dried over 4A molecular sieves). The reaction mixture was stripped to dryness on a rotary evaporator. A white solid was obtained which was recrystallized form ethanol and dried in vacuo overnight at 80° C., to give 147.45 g (92.6% yield) of white crystalline product, mp 58°-63° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]([CH3:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C(C)=CC=CC=1C>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[C:19]([CH3:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([CH:22]([CH3:24])[CH3:23])[CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(Sc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c(O)c1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)c1cc(Sc2ccc([N+](=O)[O-])cc2)cc(C(=O)O)c1O
Product: Cc1c(Sc2ccc([N+](=O)[O-])cc2)cc(C(C)C)c(O)c1C(=O)O

Procedure:
Those of the starting materials which are 5-arylthiosalicylic acids may be prepared using a similar procedure to that described for 5-(4-nitrophenylthio)-3-t-butyl-6-methylsalicylic acid in Example 2, except that pyridine is replaced by 2,6-lutidine in the preparation of the arylsulphenyl chloride. Thus there are obtained 5-(4-nitrophenylthio)-3-isopropyl-6-methylsalicylic acid, m.p. 177°-179° C. and 5-(4-nitrophenylthio)-3-t-butylsalicylic acid, m.p. 184°-185° C., from the reaction of 4-nitrophenylsulphenyl chloride with 3-isopropyl-6-methylsalicylic acid and 3-t-butylsalicylic acid respectively.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][CH2:19]3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[Br:28]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:28][C:18]1[CH2:19][C:20]2[C:16]([CH:17]=1)=[C:15]([C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[CH:23]=[CH:22][CH:21]=2
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=CC3)cc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A cold solution (5° C.) of compound 5 (49 g, 161 mmol, 1 equiv), dimethyl sulfoxide (500 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (43 g, 241 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and the mixture extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in toluene (500 mL) and p-toluenesulfonic acid (6.2 g, 32.6 mmol, 0.2 equiv) was added. The mixture was refluxed for 20 hours while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg) eluting with heptanes to give compound 6 (41 g, 66% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([N+:15]([O-])=O)[CH:5]=1.[H][H]>CO.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH2:15])[CH:5]=1
Reactant: COC(=O)c1cc(-c2ncco2)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(-c2ncco2)c1

Procedure:
A solution of 11.7 g (47.1 mmol) of 3-nitro-5-oxazol-2-yl-benzoic acid methyl ester in 1 l of MeOH and 200 ml of THF is stirred under an atmosphere of hydrogen in the presence of 0.6 g of Pd/C (10%) until the hydrogen up-take ceases. The mixture is filtered over high-flow, and the filtrate is washed with THF and evaporated to yield the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:8][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)([CH3:20])[CH3:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(CN)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNc1cccc(Br)n1)c1ccc(F)cc1
Temperature: 137 °C
Yield: 13.6 %

Procedure:
To a 5 mL microwave reaction vial was added 2,6-dibromopyridine (1.25 g, 5.0 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (1.06 g, 6 mmol, 1.2 equiv), DIPEA (1.9 mL, 11.0 mmol, 2.2 equiv), and acetonitrile (5 mL). The vial was sealed and heated in an oil bath at 137° C. for 48 h, concentrated, and purified by silica gel column chromatography to give 220 mg (14%) of 6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine as a white solid (m/z [M+H]=323).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17][CH3:18])=[CH:9][CH:10]=3)[C@@:5]3([CH2:23][O:22][CH2:21][C:20](=S)[NH:19]3)[C:4]=2[CH:3]=1.[NH3:25]>O1CCOCC1.[Hg](Cl)Cl>[Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17][CH3:18])=[CH:9][CH:10]=3)[C@:5]3([N:19]=[C:20]([NH2:25])[CH2:21][O:22][CH2:23]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)[C@@]1(COCC(=S)N1)c1cc(Br)cc(F)c1O2
Reactant: N
Agent: Cl[Hg]Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)cc(F)c1O2
Temperature: 55 °C
Yield: 46.3 %

Procedure:
In a 350-mL resealable vessel, the (S)-2′-bromo-4′-fluoro-7′-methoxyspiro[morpholine-3,9′-xanthene]-5-thione (3.0 g, 7.31 mmol) was dissolved in a dioxane solution of ammonia (0.5 M, 175 mL, 88 mmol). Mercury (II) chloride (2.98 g, 10.97 mmol) was added, and the vessel was sealed and heated in a 55° C. oil bath overnight. The reaction was cooled and then filtered through Celite, rinsing with 10% MeOH-DCM. The filtrate was concentrated, and the residue was transferred to a resealable vessel with 50 mL of dioxane. A solution of ammonia in dioxane (0.5 M, 100 mL, 50 mmol) was added, followed by mercury (II) chloride (2.0 g, 7.36 mmol). The vessel was sealed and heated in a 60° C. oil bath for 14 h. The mixture was cooled and filtered through Celite, rinsing with 10% MeOH-DCM. The filtrate was concentrated, and the residue was purified through silica gel (300 mL) using 7.5% MeOH-DCM to afford 1.33 g of (S)-2′-bromo-4′-fluoro-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20]O>S(Cl)(Cl)=O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:20])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 22.25 g of [p-(p-cyanophenoxy)phenyl]acetic acid in 55 ml of thionyl chloride is refluxed for one hour. The solvent is removed under vacuum, benzene is added (three times) and the solvent removed under vacuum. The residue is dissolved in 135 ml of methanol and stirred at room temperature for 1 hour. The solvent is removed under vacuum to give a gum. The gum is dissolved in 50 ml of warm methanol and the solution is chilled and filtered to give the product, mp 58°-60° C.
Reaction SMILES: CCO[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:21](O)(=O)[CH3:22]>>[CH2:21]([N:20]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:4](=[O:5])[N:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:22]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(=O)O
Product: CCn1c2c(c(=O)n1-c1ccccc1)CCCC2
Temperature: 120 °C

Procedure:
To a solution of cyclohexanone-2-carboxylic acid ethylester (0.6 g) in acetic acid (1 mL) in a round bottom flask under argon was added phenylhydrazine (0.38 g). The mixture was immersed into an oil bath and heated to 120° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo and azeotroped with toluene (2×). The crude residue was then purified via ISCO Combiflash chromatography (eluting with EtOAc/heptane) to afford the desired 2-phenyl-1,2,4,5,6,7-hexahydro-indazol-3-one (0.56 g) as a light brown solid. MS (ESI+): 215.4 ([M+H]+).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH3:20])[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-methyl-benzoic acid (29 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered then purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 23 mg (25%) of N-Biphenyl-4-yl-3-[4-(2-methyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 442.21 (M+1)+, 95.7%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.42 (t, 2H), 7.32 (t, 2H), 7.22 (m, 1H), 7.16 (d, 1H), 3.8 (m, 4H), 3.5 (m, 4H), 3.3 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:20](=[O:22])=[O:21].C1(C)C=CC=CC=1>CCOCC>[OH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:20]([OH:22])=[O:21])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: O=C=O
Reactant: Cc1sc2cc(CCO)ccc2c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1sc2cc(CCO)ccc2c1C(=O)O

Procedure:
Successive treatment of 3-bromo-6-(2-hydroxyethyl)-2-methylbenzo[b]thiophene with n-butyl lithium in ether followed by carbon dioxide according to the method of Example 11(ii) gave 6-(2-hydroxyethyl)-2-methylbenzo[b]thiophene-3-carboxylic acid, m.p. 166°-169° C. (from toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-methyl-1H-pyridin-2-one (15 g, 68 mmol) and phosphoryl chloride (31.1 mL, 341 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a brown solid (12.3 g, 75%). MS (ISP) 238.1 [(M+H)+], 240 [(M+2+H)+] and 242 [(M+4+H)+].