Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](Cl)(Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15](=[O:29])[C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:17][CH2:18][CH2:19][CH2:20][OH:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]2(=[O:10])[N:17]([C@H:16]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:15]([O:14][CH3:13])=[O:29])[CH2:18][CH2:19][CH2:20][O:21]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(Cl)Cl)cc1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCCO
Product: COC(=O)[C@@H](Cc1ccccc1)N1CCCOP1(=O)c1ccc(OC)cc1

Procedure:
Starting materials: 4-Methoxyphenylphosphonic dichloride and N-(3-hydroxypropyl)-D-phenylalanine methyl ester.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][C:15]2[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:14]1=2.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[C:22]([C:18]1[C:15]2[CH:16]=[C:17]([B:25]([OH:30])[OH:26])[S:13][C:14]=2[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(O)c1cccc2sccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cccc2sc(B(O)O)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
n-Butyllithium (2.5 M, 94 mL) is added dropwise to a stirred solution of diisopropylamine (33.0 mL, 235 mmol) in anhydrous THF (300 mL) at −78° C. under nitrogen atmosphere. After 30 minutes, a solution of benzo[b]thiophene-4-carboxylic acid (20.0 g, 112 mmol) in anhydrous THF (300 mL) is added. Upon the completion of addition, the reaction mixture is allowed to warm up to 0° C. where it is stirred for another 2 hours. The reaction mixture is cooled to −30° C. before it is treated with triisopropyl borate (65.0 mL, 282 mmol). The cooling bath is then removed and the reaction is allowed to reach ambient temperature where it is carefully quenched with concentrated HCl (200 mL). After evaporation of THF a suspension is formed, the solid is collected by filtration, washed twice with water (150 mL×2) and dried to provide the title compound as a white solid (20.0 g, 80% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.IC.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
To a stirred solution of 4-bromo-2,6-dimethylbenzoic acid (2.81 g, 12.3 mmol) in DMF (30 mL) was added iodomethane (2.30 mL, 36.9 mmol) and potassium carbonate (5.09 g, 36.9 mmol) and reaction was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure to yield an amber oil (3.06 g). 1H NMR (300 MHz, CDCl3): δ 7.22 (S, 2H), 3.92 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: O.[C:2]1([C:8](B(O)O)=[CH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]1[N:19]=[C:18]2[S:20][C:21]([CH3:23])=[N:22][C:17]2=[CH:16][CH:15]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:23][C:21]1[S:20][C:18]2[C:17]([N:22]=1)=[CH:16][CH:15]=[C:14]([C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH2:9])[N:19]=2
Reactant: Cc1nc2ccc(Cl)nc2s1
Reactant: C=C(B(O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1ccc2nc(C)sc2n1
Temperature: 90 °C

Procedure:
A 1000 mL rbf was charged with 1-phenylvinylboronic acid hydrate (36.7 g, 221 mmol), (amphos)2PdCl2 (3.26 g, 4.60 mmol), and 5-chloro-2-methylthiazolo[5,4-b]pyridine (34.0 g, 184 mmol) under argon. Dioxane (200 mL) was added followed by a solution of potassium carbonate (61.1 g, 442 mmol) in 60 mL water, and the reaction was fitted with a water cooled reflux condenser and flushed with argon. The resulting slurry was heated to 90° C. for 3 h. The reaction mixture was allowed to cool, and was diluted with 200 mL MTBE and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick brown oil. The oil was purified by silica gel chromatography, 0-30% EA/hexanes to give 2-methyl-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine as a brown oil. MS (ESI) m/z: calculated: 252.1; Observed: 253.1 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[N:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[N:31][CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridazin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M45) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (110 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[OH:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:12]=[CH:13][N:14]=2)=[C:2]([CH:7]=1)[O:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: N#Cc1ccc(CO)cc1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(C#N)cc3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 4-hydroxymethyl-benzonitrile (107 mg; 0.789 mmol), example 90 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>O1CCCC1.CCCCCCC>[CH3:21][C:22]1[CH:23]=[C:24]([CH2:25][CH2:1][C:2]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1cc(C)c(C(=O)O)cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(CCc2cc(C)c(C)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product of step (i)(36.7 g) in tetrahydrofuran (300 ml) was added dropwise to a stirred solution of lithium diisopropylamide (235 ml of a 2.0M solution in heptane) at 10-20° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes then cooled to -20° C. A solution of 3-methylbenzylbromide (36.2 ml) in tetrahydrofuran (100 ml) was added dropwise over 20 minutes. The mixture was allowed to warm to room temperature and stirred for 45 minutes before quenching with 2M HCl and adding ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated under reduced pressure to 200 ml. Isohexane (200 ml) was added and the crystallised unreacted starting material filtered off. The filtrate was evaporated and the residue partitioned between 2M sodium hydroxide and isohexane. The aqueous phase was acidified to pH 1 with 2M HCl and extracted with dichloromethane. The extract was dried (MgSO4) and evaporated under reduced pressure. Used directly in the next step.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:38])/[C:13](=[N:27]\[O:28][C@@H:29]([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:39])[N:8]2[S:40]([OH:43])(=[O:42])=[O:41])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:38])/[C:13](=[N:27]\[O:28][C@@H:29]([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:39])[N:8]2[S:40]([OH:43])(=[O:41])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@H](O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(N)n1)C(=O)O
Yield: 44.9 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (23 mg, 0.036 mmol), DCM (357 μL) and TFA (165 μL, 2.14 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (7.9 mg, 36%) as a white powder. LCMS: Rt=0.40 min, m/z=489.0 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 8.69 (s, 1H), 8.18 (s, 1H), 7.20 (s, 1H), 5.54 (d, J=5.7 Hz, 1H), 4.96-4.67 (m, 4H assumed; partially obscured by solvent residual peak), 1.44 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=CC=C(C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]=[CH:14][CH:15]=[CH2:16]>CC1C=CC=CC=1C>[CH3:13][C:14]1[CH:6]=[CH:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][C:16]=2[CH:15]=1
Reactant: C=CC=C
Reactant: Cc1cccc2c(C)cccc12
Solvent: Cc1ccccc1C
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
The present inventors synthesized 1,5-DMN from o-xylene and butadiene as the starting raw materials and isomerized the resultant 1,5-DMN to obtain the mixture of isomers consisting essentially of 1,5-, 1,6- and 2,6-DMNs, which was cooled as it is to precipitate 2,6-DMN crystal in the form of scale. The crystal thus obtained was poor in the efficiency of separation from the mother liquor at the time of filtration, whereby it was difficult to obtain highly pure 2,6-DMN. As is the case with the foregoing, 2,6-DMN crystal in the form of scale was obtained from the mixture of isomers containing 2,7-, 1,7-DMN, etc. other than 1,5-, 1,6- and 2,6-DMN as the starting raw material for crystallization, but it was extremely poor in filtration efficiency.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[NH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:14][NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Reactant: CCOC(N)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC=C(C(=O)OCC)c1ccc(Cl)cc1
Yield: 73.4 %

Procedure:
Then, 14.2 g of ethyl p-chlorophenyl-(α-formyl)acetate and 6.5 g of urethane were added to 50 ml of toluene containing 0.3 ml of concentrated sulfuric acid, and the mixture was heated at reflux while distilling out water which was formed during the reaction until no further water was distilled out. Thereafter, the solvent was distilled off, and the residue was extracted with diethyl ether while hot. The solvent was distilled off from the extract to obtain 13.7 g of ethyl p-chlorophenyl-(α-ethoxycarbonylaminomethylene)acetate having a melting point of 72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([O:17]CC)=O)=[C:5]2[OH:20].[C:21]([NH:30][NH2:31])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:31][NH:30][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])=[C:5]2[OH:20]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(CC)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Cl)ccc2n(CC)c1=O

Procedure:
Reagents: Comp 38 (0.68 mmols, 0.2 g); octanoyl hydrazine (0.74 mmols, 0.119 g). Yield: 0.19 g (70%), white solid, m.p.=160° C.-161° C.
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:11][CH:10]=1
Reactant: Sc1ccc(Br)cc1
Reactant: IC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1ccc(SC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-Iodotetrahydropyran (9 g, 42.45 mmol) was added to a stirred suspension of 4-bromobenzenethiol (7.296 g, 38.59 mmol) and potassium carbonate (10.67 g, 77.18 mmol) in DMF (15 mL) and the reaction stirred at ambient temperature for 3 hours. The mixture was diluted with Et2O and washed with water (×2) and brine (×1). The organic extracts was dried (MgSO4) and concentrated in vacuo. Petroleum ether was added to the residue and the resultant precipitate removed by filtration. The filtrate was concentrated in vacuo to give the sub-title compound as a light yellow oil (9.0 g, 85% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.63-1.73 (m, 2H), 1.89-1.93 (m, 2H), 3.23-3.30 (m, 1H), 3.45 (td, 2H), 3.99 (dt, 2H), 7.31 (d, 2H) and 7.45 (d, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:21]=[CH:20][C:19]([C:22]([NH2:24])=[O:23])=[C:18]2[C:10]=1[C:11]1[CH2:12][CH2:13][CH:14]([C:25](N(OC)C)=[O:26])[CH2:15][C:16]=1[NH:17]2.[CH3:31][Mg]Br.Cl>C1COCC1>[C:25]([CH:14]1[CH2:13][CH2:12][C:11]2[C:10]3[C:18](=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=[CH:21][C:9]=3[C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[NH:17][C:16]=2[CH2:15]1)(=[O:26])[CH3:31]
Reactant: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide (Example 26-1, 719 mg, 1.739 mmol) in THF (1 mL) was treated with methylmagnesium bromide (3 M in diethyl ether, 2.90 mL, 8.70 mmol) at 0° C. After 20 min, additional methylmagnesium bromide (2.90 mL, 8.70 mmol) was added and stirring was continued for 30 min more. The mixture was treated with 1 M hydrochloric acid and extracted four times with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) and the resulting material was triturated with DCM to provide 2-acetyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as an off-white solid (210 mg, 33%). 1H NMR (400 MHz, methanol-d4) δ 7.59 (1H, d, J=7.91 Hz), 7.39-7.49 (2H, m), 7.01-7.09 (3H, m), 6.90 (1H, d, J=7.91 Hz), 2.86-2.97 (3H, m), 2.24-2.33 (1H, m), 2.22 (3H, s), 2.01-2.18 (2H, m), 1.54-1.66 (1H, m). Mass spectrum m/z 369.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1>O1CCCC1.O>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]([OH:42])[CH2:1][C:2]2[C:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)=[C:5]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:4][N:3]=2)=[CH:39][CH:38]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1noc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2c(CC(O)c3ccc(Cl)cc3)noc2-c2ccccc2)cc1
Temperature: -40 °C
Yield: 45.3 %

Procedure:
To a cold (-70° C.) solution of 4-[3-methyl-5-phenylisoxazol-4-yl]benzenesulfonamide (Example 13) (250 mg, 0.8 mmol) and tetramethylethylenediamine (277 mg, 2.4 mmol) in tetrahydrofuran (5 mL) under an argon atmosphere was added n-butyllithium (1.3 mL of 1.84M in hexane, 2.4 mmol). The solution was warmed to -40° C. for 15 minutes, recooled to -70° C., and a solution of 4-chlorobenzaldehyde (337 mg, 2.4 mmol) in tetrahydrofuran (3 mL) was added. The mixture was warmed to room temperature over 30 minutes, poured into water (25 mL) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was chromatographed on silica gel using mixtures of acetone and hexane as eluents to give 165 mg of desired product as a crystalline solid: mp 165°-167° C. Anal. Calc'd. for C23H19ClN2O4S(454.93): C, 60.72; H, 4.21; N, 6.16; S, 7.05. Found: C, 60.33; H, 4.34; N, 5.87; S, 6.74.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(I)cc1N
Solvent: ClCCl
Product: CC(=O)Nc1cc(I)ccc1C
Temperature: 50 °C

Procedure:
A solution of 5-iodo-2-methyl-phenylamine (20.4 g, 87.6 mmol) in 200 mL of dry CH2Cl2 was cooled to 0° C. and acetic anhydride (16.5 mL, 175 mmol) was added dropwise. The mixture was heated to 50° C. for 2 h and then cooled to 22° C. The resulting white precipitate was filtered to give c (18.4 g, 76%): MS m/z═276 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:25]([OH:27])=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(O)(=O)C>CN(C)C=O>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36](=[O:41])[CH2:35][O:26][C:25]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:22])[Cl:23])=[O:18])[CH2:12]1)=[O:27]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCN(C(=O)OCC(Cl)(Cl)Cl)C1
Temperature: 60 °C

Procedure:
A mixture of piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl ester (3.9 g 8.8 mmol), potassium carbonate (1.83 g 13 mmol) and bromopinacolone (2.31 g 13 mmol) in N,N-dimethylformamide (55 mL) is heated at 60° C. for 2 h. The mixture is cooled back to room temperature, neutralized with acetic acid (13 mmol) and concentrated under reduced pressure. the residue is dissolved in ethyl acetate, washed with water and concentrated. Cristallization in diethyl oxide gives piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester melting at 114° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])(C)(C)C.[CH:19](N1CCOCC1)=[O:20]>C1COCC1.CCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: O=CN1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-bromo-2-(trifluoromethoxy)iodobenzene (9.93 g, 28 mmol) in THF (150 mL) at -78° C. was added tert-butyllithium (37 mL of a 1.5 M solution in pentane, 56 mmol) dropwise over a period of 20 min. The pale yellow solution was stirred at -78° C. for 1.5 h when N-formylmorpholine (6.5 mL; 58 mmol) was added. The resulting solution was stirred at -78° C. for 15 min and the cooling bath was removed. The mixture was stirred for an additional 1 h, when 0.25 M aqueous citric acid (100 mL) was added. The mixture was diluted with EtOAc (150 mL), the layers were separated, the organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified using pressurized silica gel column chromatography eluting with hexane to give 4-bromo-2-(trifluoro-methoxy)benzaldehyde as a colorless liquid (TLC Rf =0.45 (hexanes)).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[N:17][CH:16]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CN(C=O)C>[Cl:21][C:18]1[N:17]=[CH:16][C:15]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6](=[O:8])[NH:7][C:2]=3[N:1]=2)=[CH:20][CH:19]=1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(Cl)nc2)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2nc(-c3ccc(Cl)nc3)[nH]c2c1=O
Temperature: 101 °C
Yield: 77.5 %

Procedure:
A mixture of N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide (2.47 g, 7.6 mmol), P2O5 was taken in DMF (20 ml) and heated at 100-102° C. for 30 minute. Reaction mixture was cooled to room temperature and cold water (60 ml) was added. Precipitated solid was filtered off to get 8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione as pale yellow solid (1.8 g, 77%).
Reaction SMILES: [OH-].[K+].[CH3:3][P:4]([C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:8])[O:5][CH2:6][CH3:7].[CH2:19]([OH:21])[CH3:20]>>[CH3:3][P:4]([C:9]1[CH:14]=[C:13]([O:21][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([N+](=O)[O-])c(P(C)(=O)OCC)c1
Reaction time: 48 h

Procedure:
To a solution of potassium hydroxide pellets (10.0 mmol) dissolved in ethanol (B 50 ml) is added ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol). The mixture is boiled for 48 hours and is then concentrated to a slurry. The residue is diluted with water, acidified with 10% HCl and extracted with ethyl acetate (2×). The combined extracts are washed with brine, dried and evaporated to yield ethyl P-methyl-2-nitro-5-ethoxyphenylphosphinate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH2:19]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:18]
Reactant: CCOc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), m-phenetidine (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (22 mg, 63%). 1H NMR (CDCl3): 8.88–8.85 (m, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.93–7.88 (m, 1H), 7.61 (s, 1H), 7.48–7.44 (m, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.05 (s, 1H), 6.89–6.81 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).