Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(=[Se])c1ccccc1Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [Se]=C(Nc1ccccc1)c1ccccc1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6 g (0.0206 mol) 2-benzylselenobenzoic acid in 60 ml dichloromethane is treated at -10° C. with 2.64 g (0.0206 mol) chloromethylenedimethyliminium chloride (Vilsmeier's reagent). After stirring for 30 minutes at 0° C. the clear reaction mixture is treated dropwise within 15 min with a solution of 1.9 g (0.04 mol) aniline and 4.21 g (0.0416 mol) triethylamine in 60 ml dichloromethane. After stirring for 48 h at room temperature the clear yellow solution is extracted with 1N HCl (100 ml) followed by water until it is neutral, the organic phase is dried over Na2SO4 and then evaporated to dryness in vacuum. The solid crude product is recrystallized from 2-propanol (220 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([CH:14]=[O:15])=[CH:8]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:8]=[C:9]([CH2:14][OH:15])[CH:10]=[CH:11][C:12]2=[O:13])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1ccc(CO)cn1Cc1ccc(Cl)cc1
Yield: 31.9 %

Procedure:
According to Scheme 16 Method B: A solution of 1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde (1 eq, 1.41 mmol, 0.35 g, Example 10 Step 1) and DIBAL (3 eq, 4.20 mmol, 4.20 mL) in THF (5 mL) was stirred for 30 min. at −78° C. and 1 hour at room temperature. After addition of AcOEt, the reaction mixture was diluted with water. The organic layer washed with saturated NH4Cl solution, dried over Na2SO4, filtered through celite and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 95/5 to afford 1-(4-chlorobenzyl)-5-(hydroxymethyl)pyridin-2(1H)-one (0.45 mmol, 0.11 g, 32%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8]C(=O)OC(C)(C)C)[C:3]=1[I:16]>Br>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:16]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Agent: Br
Product: Nc1nccc(Cl)c1I
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The solution of tert-butyl 4-chloro-3-iodopyridin-2-ylcarbamate (3.2 g, 9 mmol) in HBr (48%, 15 mL) was allowed to stir at 100° C. for 1 h. The reaction mixture was concentrated and the resulting residue was neutralized with aqueous Na2CO3, extracted with EtOAc (2×25 mL), dried over Na2SO4, filtered and concentrated to used in next step directly without further purification. LC/MS m/z=255.19 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O.O1CCCC1>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:4][CH:3]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1ccc(N)cn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)cn1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 3-amino-6-(methylsulfonyl)pyridine (3.72 g, 21.6 mmol) in concentrated hydrochloric acid (30 mL), sodium nitrite (1.78 g, 25.7 mmol) in water (20 mL) was added dropwise at −10° C. to −15° C. and the mixture was stirred for 2 hours at −10° C to −5° C. (Note: the reaction was monitored by thin layer chromatography to make sure all the starting material was consumed). Tin(II) chloride dihydrate (20 g, 88.6 mmol) in concentrated hydrochloric acid (30 mL) was added dropwise at −5° C. The mixture was stirred 1 hour at −5° C. and then left overnight. The mixture was basified with aqueous sodium hydroxide (pH=9) with ice cooling and tetrahydrofuran (200 mL) was added and stirred for 30 minutes. The mixture was filtered by Celite® and the filtrate was extracted with tetrahydrofuran (200 mL×3). The organic extraction was combined and dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound (3.2 g, 78.8%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:13][C:14]([NH2:16])=[O:15]>CN(C=O)C>[N:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=O)CI
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of indole (10 g; 0.085 mol) in DMF (50 mL) was added dropwise to an ice cooled suspension of NaH (supplied as 60% dispersion in mineral oil) (4.1 g; 0.10 mol) in DMF (100 mL). The reaction was allowed to warm to room temperature and stirred for 4 hours until all NaH was consumed. A solution of iodoacetamide (18.5 g; 0.1 mol) in DMF (50 mL) was added and the reaction left to stir at room temperature overnight. The DMF was removed in vacuo and the residue dissolved in ethyl acetate (1 L). The organic solution was washed with water until the washings were clear (3×500 mL), brine (500 mL), dried over anhydrous magnesium sulfate and the solvent removed in vacuo. Recrystallisation from ethyl acetate provided intermediate C1 as an off white solid (9.20 g, 62%). m.p. 177–179° C. 1H NMR (500 MHz, DMSO-d6) δ 4.79 (2H, s), 6.44 (1H, dd, J 3.1, 0.7), 7.03 (1H, ddd, J 7.8, 7.8, 0.9), 7.13 (1H, ddd, J 8.2, 8.2, 1.0), 7.24 (1H, br), 7.31 (1H, d, J 3.1), 7.35 (1H, dd, J 8.2, 0.6), 7.50 (1H, br), 7.55 (1H, d, J 7.8).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:13])([C:9]([F:12])([F:11])[F:10])[CH2:5][C:4](=[O:14])[CH:3]=1.[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:13])([C:9]([F:10])([F:11])[F:12])[CH2:5][C:4]2([O:17][CH2:16][CH2:15][O:14]2)[CH:3]=1
Reactant: CC1=CC(=O)CC(C)(C(F)(F)F)C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CC2(CC(C)(C(F)(F)F)C1=O)OCCO2
Temperature: 25 °C
Yield: 90.6 %

Procedure:
2.64 g (12.8 mmole) of 3,5-dimethyl-5-trifluoromethyl-2-cyclohexen- 1,4-dione(A-5) prepared in Example 6 and 1.59 g (25.6 mmole) ethylene glycol were mixed with 250 ml of toluene, and 0.1 g of p-toluenesulfonic acid was added as catalyst. After cooling to room temperature, the reaction mixture was washed with water and aqueous solution of sodium bicarbonate. The organic layer thus formed was dried using anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was fractionated with column chromatography using n-hexane/ethyl acetate(5:1, v/v) as eluent to produce the title compound(yield: 90.6%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:4][C:3]=1[O:15][CH3:16].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[CH2:24]([NH:31][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:15][CH3:16])[CH:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(/C=C/C=C/C(=O)O)ccc1O
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C=C/C(=O)NCc2ccccc2)ccc1O
Temperature: 0 °C

Procedure:
5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid (110 mg, 0.5 mmol) [Example 3] was dissolved in 100 mL of DMF. Triethylamine (101 μl, 1.0 mmol) was added, the mixture was cooled down to 0° C. and a solution of benzylamine (109 μl, 1.0 mmol) was added followed by addition of BOP reagent (331 mg, 0.75 mmol) in 50 mL of dichloromethane.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.[CH3:14][C:15](N(C)C)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH:1]([N:4]1[C:8]([C:15](=[O:16])[CH3:14])=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC(C)n1cncn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ncnn1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 1-isopropyl-1H-[1,2,4]triazole (33 g, 300 mmol) in THF at −10° C. was added n-butyllithium (145 mL, 2.5M, 360 mmol) dropwise over 45 min, and then the mixture stirred at 0° C. for 30 min. DMA (35 mL) was added, the mixture allowed to warm to RT and stirred for 1 h. The resultant suspension was treated with saturated aqueous ammonium chloride (300 mL). The aqueous phase was extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give 1-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone as a pale orange oil (40.1 g, 87%). 1H NMR δ (ppm) (CDCl3): 7.93 (1H, s), 5.58-5.46 (1H, m), 2.72 (3H, d, J=0.78 Hz), 1.49 (6H, dd, J=6.61, 0.78 Hz).
Reaction SMILES: [Sn].[Cl-].[C:3]([OH:12])(=[O:11])[CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])O>[Pd].[Cu]>[C:8]([OH:10])(=[O:9])[CH2:6][C:6]([CH2:4][C:3]([OH:12])=[O:11])([C:8]([OH:10])=[O:9])[OH:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [Cu]
Agent: [Pd]
Agent: [Cl-]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
An activator bath of this invention in its preferred embodiment, comprising 0.0597 gm./l. palladium and 3 gm./l. tin, chloride normality of 3.6N, 7.5 gm./l. tartaric acid and 3.0 gm./l. citric acid was prepared. Copper clad laminates were subjected to the plating process of this invention. Analysis verified that the bath contained 0.0597 gm./l. palladium and 3 gm./l. stannous ion. Absorption data showed 0.8 mg./sq. cm. palladium and 2076 mg./sq. cm. tin on the substrate after activation. Good copper coverage and no voids were found after electroless copper plating.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=2)[CH2:18][CH2:17]1)=[O:13].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[S:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=2)[CH2:18][CH2:17]1)=[O:13]
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[nH]nc(C(=O)NCC3CCN(Cc4nc(C(=O)O)cs4)CC3)c2c1
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of compound 7 (1.85 mmoles) in MeOH (10 mL) aqueous 1M NaOH (3.7 mL) was added. The solution was refluxed overnight then the organic solvent was removed under vacuum, the residue was diluted with H2O and the pH was adjusted to 5 by adding 1M HCl. The mixture was kept at 4° C. overnight then the resulting solid was filtered, washed with fresh water and dried under vacuum to give 2-{[4-({[(5-Methoxy-1H-indazol-3-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}-1,3-thiazole-4-carboxylic acid 8 (43% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N+:9]([O-])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:18])=O.O.[OH-].[Li+]>O1CCCC1>[Cl:18][C:8]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc[n+]([O-])c(C(F)(F)F)c1F
Reactant: O=P(Cl)(Cl)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid 1-oxide (1.0 g, 4.4 mmol from Step A) in phosphoryl chloride (4 mL, 40 mmol) was heated to 110° C. for 2 hours, then was left to stir at ambient temperature overnight. The POCl3 was evaporated, the residue was treated with sodium bicarbonate solution, which was stirred for 1 hour. To this mixture was added tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (0.24 g, 5.7 mmol). This was stirred for 3 hours. The pH of the mixture was then adjusted to the range of pH 4-5 by the addition of c.HCl. The product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Yield: 0.54 g (50%); LC-MS: 244.1/245.9 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[ClH:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][Cl:16].Cl>CN(C=O)C.O>[ClH:16].[ClH:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: Nc1cccc(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 3-aminophenol (10.9 g, 100 mmol) in DMF (100 mL) cooled with an ice/H2O bath was added NaH (8.90 g, 222 mmol) in 4 portions. 2-(Dimethylamino)ethylchloride hydrochloride (15.8 g, 110 mmol) was then added in 3 portions and the reaction was stirred at rt overnight. The reaction was poured into H2O (600 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (flash chromatography), treatment with HCl (50.0 mL, 4M in dioxane, 200 mmol) and concentration provided the title compound (14.0 g, 56.0 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (s, 6H), 3.46 (t, J=4.8 Hz, 2H), 4.30 (t, J=4.9 Hz, 2H), 6.58-6.66 (m, 3H), 7.18 (t, J=8.2 Hz, 1H), 8.55 (br.s., 2H), 10.70 (br.s., 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Reactant: OB(O)c1cccnc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.14 g, 0.4 mmol) and commercially available 3-pyridylboronic acid (0.049 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.027 g, 19%). MS (ISN) 346.1 [(M−H)−]; mp 179-181° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:35]=[CH:36][CH:37]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@H:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:38]([BH3-])#N.[Na+]>CO.C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:35]=[CH:36][CH:37]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@H:28]([N:30]([CH2:31][CH2:32][O:33][CH3:34])[CH3:38])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: [BH3-]C#N
Reactant: COCCN[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COCCN(C)[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Add to a solution of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-N—[(R)-6-(2-methoxy-ethylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide (0.13 g, 0.20 mmol) in 5 mL MeOH formalin (0.3 mL) and sodium cyanoborohydride (51 mg, 0.82 mmol). Stir the mixture at room temperature for 2 h. Add sat. NH4Cl to the mixture to quench any unreacted sodium cyanoborohydride. Concentrate the mixture, concentrate and purify via preparative HPLC to afford 0.06 g, 58% yield of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-N-{(R)-6-[(2-methoxy-ethyl)-methyl-amino]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-benzamide. MS, ES+ 528.44 (M+H), rt 5.33 min
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:22])[C:3]=1[C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1.C(N(CC)CC)C.Cl.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH3:22])[C:3]=1[C:23]1[N:24]=[C:25]([NH:28][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[S:26][CH:27]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-amine (26-4, 0.500 g, 1.29 mmol) in THF (6.4 mL) was added triethylamine (0.39 g, 3.86 mmol) followed by isonicotinoyl chloride hydrochloride (0.46 g, 2.58 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and dried to give N-{4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-yl}isonicotinamide (26, 0.51 g) as light yellow solids in 80% yield: 1H NMR (500 MHz, CDCl3) δ 8.72 (m, 2 H), 7.61 (m, 2 H), 7.31-7.34 (m, 2 H), 7.08-7.10 (m, 1 H), 6.94-7.02 (m, 6 H), 6.80 (s, 1H), 6.49 (s, 2 H), 1.94 (s, 6 H). ESI-MS: m/z 494.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24].N.C(Cl)Cl>CC#N.CO>[NH2:24][CH2:23][CH2:22][NH:25][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: NCCN
Reactant: Cc1cc(Cl)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Agent: N
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C

Procedure:
Dissolve 7-chloro-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a] pyrimidine in 25 mL CH3CN, then add excess ethylenediamine (5 mL) and heat to 80° C. for 3-6 h under N2 with attached reflux condenser. (TLC; product diamine Rf=0.5, aryl chloride Rf=1.0; [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent). Cool to ambient temperature and evaporate to yellow oil. Partition between CH2Cl2 (50 mL) and 1.0 N NaOH (50 mL), and extract aqueous layer 2×30 mL CH2Cl2. Pool organic layers, dry over Na2SO4, filter and evaporate to yellow-white foam (1.25 g). Use without further purification. LCMS=344.4 (MH+); 342.3 (M−).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1)(=[O:4])=[O:3].[C:16](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:16][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1coc(N(C)S(C)(=O)=O)n1
Reaction time: 3 h

Procedure:
To a 25 ml round bottom flask under N2 was added (101.8mg, 0.4346 mmoles) ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate, (180.2 mg, 1.3038 mmoles, 3.0 eq.) potassium carbonate, and (5 ml) acetonitrile. The mixture was then agitated at ambient temperature while (33.8 μl, 0.5429 mmoles, 1.25 eq.) iodomethane was added. The reaction was allowed to run at ambient temperature for 3 hours. An electrospray mass spec indicated mostly starting material. The N2 line was removed and an additional (40 μl, 0.6425 mmoles, 1.5 eq.) iodomethane were added. The reaction was left at ambient temperature overnight. The reaction was quenched with (5 ml) 1N HCl and was extracted with dichloromethane. The organic layer was washed with water and then evaporated to dryness. The resulting oil was purified by preparative HPLC, yielding (70 mg) of ethyl 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1
Yield: 32 %

Procedure:
1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210° C.; MS: 432 (M+H)+.
Reaction SMILES: ClC1C=C(SC2C3C(=CC(C)=CC=3)[NH:12]C=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:27]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][C:45]([OH:47])=O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.C(Cl)(=O)C(Cl)=O.N>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][C:45]([NH2:12])=[O:47])[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CC(=O)O)[nH]c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CC(N)=O)[nH]c2c1
Yield: 80 %

Procedure:
Following the method used to prepare 24a, the use of 53 (0.35 g, 0.96 mmol) and oxalyl chloride (120 μL, 1.44 mmol) followed by allowing the intermediate acid chloride to react with ammonia in dioxane provided 0.28 g (80%) of product 24b as an off white solid, mp 197° C. 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 3.70 (s, 2H), 6.90 (d, J=8 Hz, 1H), 6.99-7.01 (m, 2H), 7.08 (brs, 1H), 7.20 (d, J=8 Hz, 1H), 7.25-7.28 (m, 2H), 7.54 (brs, 1H), 11.65 (brs, 1H). LC-MS (CI): m/z 365.0, 367.0 [(M+H)+ C17H14Cl2NO2S requires 364.0]. Purity (100%). Calcd for C17H14Cl2NO2S: C, 55.90; H, 3.86; N, 7.67; S, 8.78; Cl, 19.41. Found: C, 55.61; H, 3.90; N, 7.68; S, 8.59; Cl, 19.67.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH2:16][F:17])[CH2:14][F:15])[C:5]([O:7]C)=[O:6].[Li+].[OH-].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH2:14][F:15])[CH2:16][F:17])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(CF)CF)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OC(CF)CF)c(Cl)c1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a solution of methyl 3-chloro-4-(1,3-difluoropropan-2-yloxy)benzoate (2.00 g, 7.56 mmol) in dioxane (15.11 mL) was added LiOH (1.0 M aq, 22.67 mL, 22.67 mmol). The reaction was stirred at 30° C. for 1.5 h in a 1 L round-bottomed flask. The reaction was cooled to room temperature and poured into 1 N HCl. A precipitate was formed and filtered by vacuum filtration to give the title compound (1.5 g) as a white solid. LCMS m/z=250.9 [M+H]+.