Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:12]=[N:11][N:10]([CH3:13])[C:9]=1[C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[OH:20].CS(O[CH2:39][C:40]([CH3:45])([N+:42]([O-:44])=[O:43])[CH3:41])(=O)=O.O>CC(N(C)C)=O>[N+:42]([C:40]([CH3:45])([CH3:41])[CH2:39][O:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:9]1[N:10]([CH3:13])[N:11]=[CH:12][C:8]=1[Cl:7])([O-:44])=[O:43]
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Cesium carbonate (815 mg, 2.50 mmol) was added to a solution of N-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (396 mg, 1.00 mmol) and 2-methyl-2-nitropropyl methanesulfonate (276 mg, 1.40 mmol) in DMA (2.0 mL) and the mixture was stirred at 160° C. After 1 hr, the mixture was allowed to cool to room temperature and poured into water, and the resulting suspension was extracted with dichloromethane. The extract was dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate—hexanes 1:2) to afford the product (338 mg, 68%) as a yellow oil. LCMS m/z (%)=499.5 (M+H 37Cl 31.5%), 497.4 (M+H 35Cl 100.0%). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (s, 3 H), 1.57 (s, 3 H), 3.64 (s, 3 H), 4.01 (d, J=9.85 Hz, 1 H), 4.49 (d, J=9.85 Hz, 1 H), 7.08 (d, J=8.84 Hz, 1 H), 7.49 (d, J=2.53 Hz, 1 H), 7.51 (s, 1 H), 7.65 (t, J=7.71 Hz, 1 H), 7.80-7.90 (m, 3 H), 8.07 (d, J=7.83 Hz, 1 H), 8.13 (s, 1H).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([O:46][CH3:47])[CH:45]=1)[CH:41]=O>C1COCC1>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:41]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])[CH:43]=[C:44]([O:46][CH3:47])[CH:45]=1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=CCC(=O)O)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (13.7 g, 33 mmol) in dry THF (50 mL) was added NaHMDS (33 mL, 66 mmol) dropwise at −20° C. under N2 and the reaction stirred for 20 min. The reaction was cooled to −78° C. and 3,5-dimethoxybenzaldehyde (5.0 g, 30 mmol) was added, and the reaction mixture stirred overnight while warming to rt. The reaction was quenched with water and extracted with EtOAc. The aqueous layer was acidified to pH=2 with dilute HCl solution and extracted with EtOAc again. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 2.54 g (38%) of the title compound as an orange gum. [M+H] Calc'd for C12H14O4, 223. Found, 223.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(OC)c2)c1C(=O)OC
Yield: 122.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol) was added 1-bromomethyl-3-methoxy-benzene (0.77 mL, 5.5 mmol) and refluxed for three hours. The solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL) and washed with water (2×50 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.1 g, 118% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:24][NH:25][CH3:26].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([N:25]([CH3:26])[CH3:24])=[O:8])([O-:3])=[O:2]
Reactant: CNC
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In an ice bath under N2-atmosphere, 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster; 11.8 g, 50 mmol), CH2Cl2 (150 ml), 3 drops of DMF and oxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 2.5 h at rt. The resulting solution is concentrated in vacuo. The residue is dissolved in CH2Cl2 (170 ml) and added dropwise to an ice cooled solution of dimethylamine hydrochloride (4.5 g, 55 mmol) and NEt3 (21 ml; 0.15 mol) in CH2Cl2 (100 ml). After stirring for 15 h at rt, the mixture is worked up as described in Stage 134.3, giving the title compound as an oil: MS: [M+1]+=263; 1H-NMR (CDCl3): 8.53 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 3.18 (s, 3H), 3.04 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:9][C:10]([F:14])([F:13])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)CI
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(OCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 3-hydroxytoluene (5.0 g, 46.2 mmol) in N,N-dimethylformamide (50 ml) were added 2,2,2-trifluoro-1-iodoethane (10.7 g, 50.9 mmol) and potassium carbonate (12.8 g, 92.5 mmol) and the mixture was stirred overnight at 80° C. The reaction solution was diluted with water (200 ml) and extracted with diethyl ether (300 ml×2). The extract was washed successively with water and saturated brine, dried-over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(2,2,2-trifluoroethoxy)toluene (7.60 g, 86%) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:13]([CH3:16])([O-:15])=[O:14]>>[N+:13]([CH:16]=[CH:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccco1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccco1
Yield: 53 %

Procedure:
2-Furaldehyde (18.2 g, 190 mmol) and ammonium acetate (13 g, 169 mmol) were added to nitromethane (169 mL) and the mixture was heated to reflux for 45 min. The solution was concentrated and dichloromethane (250 mL) was added. The dichloromethane solution was washed with water (2×250 mL), dried over sodium sulfate, and filtered to obtain the crude product. Purification by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 2/3) afforded pure 2-(2-nitrovinyl)-furan (14 g, 53.0%) as a yellow powder (M.P. 71-74° C.). 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.78 (d, 1H, J=13.2 Hz), 7.59 (m, 1H), 7.52 (d, 1H, J=13.5 Hz), 6.90 (d, 1H, J=3.6 Hz), 6.58 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 146.90, 146.67, 134.93, 125.51, 120.12, 113.46.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(OCC1C=CC=CC=1)=O.C(O)(=O)C>CO.[Pd]>[C:31]([O:30][CH:24]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(COc1ccccc1CCCCNC(=O)OCc1ccccc1)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OCC(COc1ccccc1CCCCN)OC(C)=O
Reaction time: 3 h
Yield: 88 %

Procedure:
Cbz-protected amine 34 (0.6 g, 1.3 mmol) was dissolved in methanol (25 mL) containing 1% acetic acid then Pd/C (0.22 g, 5% wet.) was added. The reaction mixture was stirred for 3 h under hydrogen (1 atm), then the solution was filtered through a pad of silica gel and the solvent was evaporated to give amine 35 (0.37 g, 86%) as a clear oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16]O>C[Re](=O)(=O)=O>[CH2:9]([N:8]([OH:16])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Product: ON(Cc1ccccc1)Cc1ccccc1
Yield: 50 %

Procedure:
U.S. Pat. No. 3,491,151 discloses a method for preparing N,N-dialkylhydroxylamine compounds by allowing hydroxylamines react with alkyl halides, alkyl tosylates or the like. However, this method is also undesirable, because it requires a prolonged reaction time and achieves a yield of no more than about 50%. Tetrahedron Letters, Vol. 37, No. 33 pp. 6025-6028, 1996 discloses a method for synthesizing nitrone compounds by oxidizing dibenzylamine by means of a combination of aqueous hydrogen peroxide and methyltrioxorhenium. According to this synthetic method, an N,N-dibenzylhydroxyl-amine compound is produced in addition to a nitrone compound as a major product. However, its yield is low. Furthermore, the method requires a large amount of methyltrioxorhenium. For these reasons, the method is only disadvantageously applied to practical preparations of N,N-dibenzylhydroxylamine compounds.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[SH-:12].[K+].O>C(O)C>[SH:12][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: [SH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc2ccc(S)nn12

Procedure:
A mixture of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]-pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971) ] (1.70 g., 0.01 mole) and potassium hydrosulfide (1.44 g., 0.02 mole) in ethanol (30 ml.) was heated in a sealed tube for 8 hours at 140°. After cooling, water (50 ml.) was added to the reaction mixture and a small amount of insoluble material was removed by filtration. The filtrate being concentrated under reduced pressure, the concentrate was acidified to pH 2 with dil. HCl to afford yellow precipitate of 6-mercapto-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one which was collected by filtration, washed with water (10 ml.) and dried in vacuo on P2O5. Yield 1.43 g. (84%). M.p. > 300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:14]3[CH:12]([CH2:13]3)[N:11](C(OCC3C=CC=CC=3)=O)[C:10]2=[O:25])[CH:6]=[CH:5][N:4]=1.Cl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[C:10](=[O:25])[NH:11][CH:12]3[CH:14]2[CH2:13]3)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(N2C(=O)N(C(=O)OCc3ccccc3)C3CC32)ccn1
Agent: Cl
Product: COc1cc(N2C(=O)NC3CC32)ccn1
Yield: 66.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 30 for the preparation of I-30c above, benzyl 4-(2-methoxypyridin-4-yl)-3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (150.0 mg, 0.442 mmol) was treated with 10.0 mL of 6N HCl to yield the crude product. Purification by column chromatography on silica gel (1.5% methanol in chloroform) afforded 60 mg of the product (67% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][CH2:17]1
Reactant: IC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(C4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:19])([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:19]
Reactant: CCCN1CCOC(c2ccc(O)c([N+](=O)[O-])c2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCN1CCOC(c2ccc(O)c(N)c2)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To the nitro from example 36 (95 mg, 0.35 mmol) in ethanol (10 ml) was added 10% palladium on charcoal (50 mg) and ammonium formate (100 mg, XS). The reaction mixture was gently heated to 70° C. and held at this temperature for 1 hour before it was allowed to cool to room temperature. The reaction mixture was then filtered through arbacel and washed with ethanol (20 ml) then dichloromethane (20 ml). The organic washes were combined and concentrated in vacuo to give the title compound as a yellow solid (65 mg, 0.28 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ: 0.91 (t, 3H), 1.55 (m, 2H), 2.12 (t, 1H), 2.25 (dt, 1H), 2.40 (t, 2H), 2.81-2.92 (dd, 2H), 3.82 (t, 1H), 4.00 (d, 1H), 4.42 (d, 1H), 6.60 (m, 2H), 6.71 (s, 1H). LRMS: m/z 237 (M−H+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]([C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH:32]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:32][C:28]2[S:29][CH:30]=[CH:31][C:27]=2[O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2sccc2Oc2ccccc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 76.3 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 3-phenoxythiophene-2-carboxaldehyde (0.300 g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 3 hours at room temperature to afford 0.331 g (76%) of the title compound as an off-white solid, mp 135-137° C.: APCI-MS m/e 443.5 (M++1).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[OH-]>CO>[C:10]1([N:16]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[CH2:18][CH:17]2[CH3:22])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClCCN1CCOCC1
Reactant: CC1CNCCN1c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC1CN(CCN2CCOCC2)CCN1c1ccccc1

Procedure:
In the same manner as described in Example 1, N-(2-chloroethyl)morpholine is reacted with 1-phenyl-2-methylpiperazine. The trihydrochloride has a melting point 288°-290° (from methanol); Rf=0.63 (MeOH-conc. NH4OH 97:3); IR (nujol) νmax: 2420, 1500, 1405, 1265, 1060, 770, 695 cm-1 ; 1H-NMR (D2O; (CH3)3Si(CD2)2COONa): 1.05 (d, J=6 Hz; 3H; 2.70-4.20 (m; 19H); 7.47 (s; 5H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@@H:22]([O:40]C=O)[C@@H:23]([CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C@@H:22]([OH:40])[C@@H:23]([CH2:27][CH2:28][N:29]3[C:30](=[O:39])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]3=[O:38])[C:24]([OH:26])=[O:25])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O=CO[C@H](CCc1ccc(-c2ccc(Cl)cc2)cc1)[C@@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)[C@H](CCN1C(=O)c2ccccc2C1=O)[C@H](O)CCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.007 g) was added to a solution of the compound obtained from step m above (0.025 g) in methanol (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 10% methanol in dichloromethane as eluant to afford the title compound (0.014 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>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>[Cl:8][C:6]1[CH:7]=[C:2]([C:20]2[CH:21]=[N:22][C:17]([O:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:18][CH:19]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)nc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
n-Butyllithium (1.6 M in hexane) (20.5 ml) was dropwised to a mixture of 5-bromo-2-(cyclohexyloxy)pyridine (7.00 g) and THF (dry) (75 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (7.71 g) was dropwised to the mixture at −78° C. and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (75 mL)/water (120 mL) and stirred for 1 hr. The organic layer was separated and the aqueous phase was washed with Et2O (100 mL×2) and neutralized by 1N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give [6-(cyclohexyloxy)pyridin-3-yl]boronic acid (5.15 g) as pale yellow solid. Tetrakis(triphenylphosphine)palladium(0) (107 mg) was added to a suspension of 3-bromo-5-chloropyridin-2-amine (640 mg), [6-(cyclohexyloxy)pyridin-3-yl]boronic acid (750 mg) and sodium carbonate (654 mg) in DME (15 mL) and water (3 ml) and the mixture was stirred at 100° C. under nitrogen for 2.5 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (846 mg) as colorless gum.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[N:26]=1)=[O:24]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[N:26]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nc(C(=O)c2cc(Cl)ccc2N)c2ccccc21
Product: Cn1nc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c2ccccc21

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using 4-tert-butyl-benzenesulfonyl chloride and (2-Amino-5-chloro-phenyl)-(1-methyl-1H-indazol-3-yl)-methanone and purified by HPLC: MS: m/z 483 (M++1).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:7]2[CH2:13][NH:12][CH2:11][CH2:10][C:8]=2[N:9]=1.I[CH2:22][CH2:23][CH3:24]>>[ClH:20].[ClH:1].[NH2:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:7]2[CH2:13][N:12]([CH2:22][CH2:23][CH3:24])[CH2:11][CH2:10][C:8]=2[N:9]=1
Reactant: CCCI
Reactant: Nc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Agent: Cl
Product: CCCN1CCc2nc(N)nc(-c3ccc(Cl)cc3)c2C1
Yield: 82.8 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride (4.0 g, 13.5 mmol) and iodopropane (1.3 mL, 13.5 mmol) instead of iodoethane to produce 2.1 g (51%) of 2-amino-4-(4-chlorophenyl)-6-propyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride 1/4 hydrate. m.p. 244°-246° C. MS: 303(HM+).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:33])([F:32])[S:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:20]=[CH:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[C:16](=[C:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:15]=2[CH:31]=1)=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:28]1[CH2:29][CH2:30][C:25](=[C:16]2[C:15]3[CH:31]=[C:11]([S:9]([C:8]([F:33])([F:7])[F:32])=[O:10])[CH:12]=[CH:13][C:14]=3[CH:20]=[CH:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]2=3)[CH2:26][CH2:27]1)[CH3:2]
Reactant: O=S(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Reactant: C1CO1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide in 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.25 g. of 4-(3-trifluoromethylsulfinyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give 1-hydroxyethyl-4-(3-trifluoromethylsulfinyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][C:23]([CH3:25])=[CH2:24])[C:10]1([CH3:37])[CH3:36])(C(C)(C)C)(C)C.C1C=CC=CC=1.[ClH:44]>C(O)C>[Cl:44][C:23]([CH2:22][CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:27]2([CH3:35])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:31]([C:30]=3[CH2:29][CH2:28]2)([CH3:34])[CH2:32][CH2:33][C@H:9]([OH:8])[C:10]4([CH3:37])[CH3:36])=[CH:16][CH2:17]1)[CH3:26])([CH3:25])[CH3:24]
Reactant: Cl
Reactant: C=C(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCO
Solvent: c1ccccc1
Product: C[C@H](CCCC(C)(C)Cl)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
A mixture of 3β-(tert-butyldimethylsilyloxy)-4,4-dimethylcholesta-5,7,25-triene (50 mg), benzene (5 mL), ethanol (5 mL) and concentrated HCl (2 mL) was heated under reflux for 4 hours. The reaction was concentrated to half volume under reduced pressure and water (5 mL) was added. Extraction of the aqueous phase with dichloromethane and concentration under reduced pressure gave a residue, which was purified by flash chromatography. Recrystallisation from ethyl acetate:hexane gave the title compound as a white solid (35 mg).