Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[NH2:30][OH:31]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:30][OH:31])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 121.9 mg, 0.29 mmol) and hydroxylamine hydrochloride (30.4 mg, 0.43 mmol) in methanol (0.85 mL) and pyridine (0.85 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 80–100% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (68.8 mg, 55%) as a white solid: mp 205–207° C.; (ES)+-HRMS m/e calcd for C19H21ClN4O4S (M+H)+ 437.1045 found 437.1048.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-chlorobenzyl)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 8): 1H-NMR (CDCl3) δ 7.98 (2H, dd, J=6.5, 1.7 Hz), 7.36–7.26 (4H, m), 7.19–7.13 (3H, m), 7.05 (1H, br.s), 6.97–6.94 (1H, m), 5.93 (1H, d, J=7.2 Hz), 5.19 (1H, dq, J=7.2, 7.0 Hz), 4.11 (2H, s), 3.92 (3H, s), 1.44 (3H, d, J=7.0 Hz); MS (ESI) m/z 442 (M+H)+, 440 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Br:15]C1C=CC=CC=1C=O>>[Br:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Reactant: O=Cc1ccccc1Br
Product: Cc1cccc(-c2ccccc2Br)n1

Procedure:
6-(2-bromophenyl)-2-methylpyridine was prepared substantially according to the procedure of Example 1 for preparing 6-(2-chlorophenyl)-2-methylpyridine except 2-bromobenzaldehyde was used to afford 6-(2-bromophenyl)-2-methylpyridine.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:2]2[CH2:7][CH2:6][O:5][C:3]2=[O:4])=[CH:12][CH:11]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C1OCCC1Br
Product: O=C1OCCC1Oc1ccc(C(F)(F)F)cc1
Yield: 46 %

Procedure:
The compound is prepared according to the experimental procedure described in Preparation 1, starting with α-bromo-γ-butyrolactone (6.7 g, 0.040 mol) and 4-trifluoromethylphenol (5.0 g, 0.031 mol) to give 3.51 g of the expected compound in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:33][C:34](=[O:36])[CH3:35])[C@H:10]([OH:32])[CH2:11][NH:12][C@@H:13]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26])[CH:21]=3)[O:16][C:15]3([CH2:31][CH2:30][CH2:29]3)[CH2:14]2)=[CH:4][CH:3]=1.CC(O)=O>CO.C(O)(N=NC(O)=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:33][C:34](=[O:36])[CH3:35])[C@H:10]([OH:32])[CH2:11][NH:12][C@@H:13]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH3:26])[CH:21]=3)[O:16][C:15]3([CH2:31][CH2:30][CH2:29]3)[CH2:14]2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)Cc1cnc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1ccc(Cl)cc1)NC(C)=O)CC1(CCC1)O2
Agent: O=C(O)N=NC(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: CCC(C)(C)Cc1cnc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1ccc(Cl)cc1)NC(C)=O)CC1(CCC1)O2

Procedure:
The compound of Example 492 (0.100 g, 0.196 mmol) was dissolved in MeOH (2 mL) and diazenedicarboxylic acid, dipotassium salt (0.762 g, 3.92 mmol) was added. HOAc (0.673 ml, 11.8 mmol) in MeOH (2 mL) was slowly added to the heterogeneous solution and the reaction was stirred. After all the acetic acid was added and the solution went from yellow to clear and upon complete reduction, the reaction was concentrated and partitioned between 1 N NaOH and DCM. The aqueous was layer was extracted with DCM and the combined organics were washed with brine and concentrated. The crude material was dissolved in a minimal amount of MeOH and directly purified by reverse phase HPLC to afford the title compound. MS m/z: 514.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][C@@H:5]([OH:18])[CH2:4]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([S:8]([N:7]2[CH2:6][C@@H:5]([O:18][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:4][C@@H:3]2[CH2:2][O:1][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@@H]2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of 5-hydroxymethyl-1-(toluene-4-sulfonyl)-pyrrolidin-3-ol (4) (0.45 g, 1.66 mmol) in pyridine (3 mL) is added 4-toluylsulfonyl chloride (1.11 g, 5.81 mmol) in one portion. The temperature rises to 50° C., then the reaction mixture is cooled to 10° C., kept at that temperature for an additional 2 h and then left at room temperature overnight. The mixture is poured into 2N HCl (13 mL). On cooling the compound precipitates out and separated by filtration, washed with cold water (2×5 mL), and dried under reduced pressure to give compound (5) as white solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH:14]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH2:14][NH:20][CH2:21][CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: CN(C(=O)CCN)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 5-benzoyl-2-nitro-benzaldehyde (10 g, 0.0390 mol), a known compound (which may be prepared as disclosed in European Patent EP 371564) and 3-amino-N-cyclohexyl-N-methyl-propionamide (7.5 g, 0.0410 mol) in 1,2-dichloroethane (250 mL) was stirred at room temperature under nitrogen. Sodium triacetoxyborohydride (8.7 g, 0.0410 mol) was added, and the reaction mixture was stirred for 6 h at room temperature. Saturated NaHCO3 solution (200 mL) was then added. The organic layer was separated, dried, and evaporated. The resulting residue was purified by column chromatography on silica gel (eluent: 99:1 CH2Cl2:MeOH). The purest fractions were combined, and the solvent was evaporated to yield a residue.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:17]([CH:14]1[CH2:16][CH2:15]1)[CH2:12]2
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccc(Br)cc2CN1C1CC1

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (Ark Pharm, Cat. No. AK-26333) (0.5 g, 0.002 mol), cyclopropylamine (0.17 mL, 0.0024 mol) and potassium carbonate (0.45 g, 0.0032 mol) in ethanol (5 mL) was stirred at 40° C. for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was directly used in nest step reaction without further purification. LCMS (M+H)+=252.0/254.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[CH:4]=1.[Li]CCCC.[I:18]I>O1CCCC1>[I:18][C:4]1[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COCOc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OC)c1I
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of 1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene (Intermediate 45, 10 g, 59.5 mmol) in tetrahydrofurane (100 ml, SCRC) precooled to −78° C. was added dropwise BuLi (2.5 M in THF, 28.5 ml, 71.3 mmol, SCRC), maintaining the inner temperature lower than −70° C. After the addition was complete, the mixture was stirred at −70° C. for 2 hours and a solution of iodine (15.09 g, 59.5 mmol, SCRC) in THF (50 ml, SCRC) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature and quenched with a saturated aqueous solution of ammonium chloride (100 ml). The mixture was extracted with ethyl acetate (3 times 300 ml, SCRC) and the combined organic layers were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc:PE (1/100) to afford the title compound (16.2 g) as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]>C(O)C.[Pd].[H][H]>[CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: CCCCCP(=O)(OCC)c1ccc(NC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCP(=O)(OCC)c1ccc(NC)c(N)c1

Procedure:
Prepared analogously to Example 1c from ethyl(4-methylamino-3-nitro-phenyl)-n-pentyl-phosphinate and palladium on activated charcoal/hydrogen in ethanol.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:23])[C:4]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5].[H-].[Na+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:12]([C@H:9]2[CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[N:3]([O:2][CH3:1])[CH3:23])[CH2:7][CH2:8]2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OCc2ccccc2)CC1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CC[C@@H](N(Cc2ccc(Cl)cc2)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of benzyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate in DMF (12 mL) under an atmosphere of nitrogen was cooled to 0° C., followed by treatment with sodium hydride (150 mg of 60 wt % NaH in oil, 3.75 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled to 0° C. and charged with 4-chlorobenzyl bromide (793 g, 3.75 mmol). The resulting solution was warmed slowly to room temperature and stirred for another 16 hr prior to partitioning of the solution between saturated aqueous NaHCO3 and ethyl acetate. The aqueous layer was further extracted with additional ethyl acetate. After separating the organic layer, the combined organic layer was washed with saturated aqueous sodium chloride, dried using MgSO4, filtered, and concentrated to give benzyl 4-chlorobenzyl(cis-4-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate as a colorless oil (1.19 g, 2.67 mmol, 86.0%). 1H NMR (CDCl3, 300 MHz) δ 7.45-7.05 (m, 9H), 5.09 (bs, 2H), 4.41 (bs, 2H), 4.30-4.04 (m, 1H), 3.65 (s, 3H), 3.14 (s, 3H), 2.91 (m, 1H), 2.02-1.84 (m, 4H), 1.70-1.47 (m, 4H).
Reaction SMILES: C[Li].[Cl-].[Cl-].[CH-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Zr+2:15]>C(OCC)C>[CH3:10][C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[C-:10]1([CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11]1.[Zr+2:15]
Reactant: c1cc[cH-]c1
Agent: [Zr+2]
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Product: C[c-]1cccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 211 %

Procedure:
Following the literature procedure [b], 3.30 ml (5.33 mmol, 1.60 M) of an ethereal solution of methyllithium are slowly added dropwise at -78° C. to a suspension of 1.03 g (2.66 mmol) of zirconocene dichloride (Example 10) in 50 ml of diethyl ether. The mixture is allowed to warm slowly to room temperature in a cold bath and is then stirred at room temperature for a further 5 hours. The solvent is removed in vacuo, and the colorless residue is extracted with 3×50 ml of pentane. The combined pentane solutions are evaporated and kept at -25° C. to crystallize. Removal of the solvent and drying in an oil-pump vacuum gives 700 mg (76%) of dimethylzirconocene as a colorless, crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:14][CH2:15]O>S(=O)(=O)(O)O>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
A solution of 3-bromo-4-methoxyphenylacetic acid (3.0 g, 12.2 mmol) in EtOH and sulfuric acid was stirred at 100° C. for 2 hours. The mixture was concentrated and partitioned between EtOAc and H2O, and the organic layer was separated to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](=[O:22])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(-c2ccco2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(-c3ccco3)n2)sc2ccccc12
Yield: 70 %

Procedure:
6-(2-Furyl)-2-pyridinecarbonitrile (0.60 g, 3.5 mmol) and methyl thiosalicylate (1.01 g, 6.0 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 12 hrs. After cooling, the precipitates were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.75 g, 69%) as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:49]=[CH:50][CH:51]=1)[CH2:42][O:43][CH2:44][C:45]#[C:46][CH2:47][OH:48].C(O)C#CCO.COC1C=C(C=CC=1)CBr>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:48][CH2:47][C:46]#[C:45][CH2:44][O:43][CH2:42][C:41]3[CH:49]=[CH:50][CH:51]=[C:39]([O:38][CH3:37])[CH:40]=3)[N:18]=[C:17]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: COc1cccc(COCC#CCO)c1
Agent: COc1cccc(CBr)c1
Agent: OCC#CCO
Product: COc1cccc(COCC#CCOc2nc(-c3ncccn3)nc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2ccccc2OC)c1
Yield: 25.7 %

Procedure:
Crude 4-tert.-butyl-N-[6-(4-(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained starting from 300 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (Example 5a) and 1096 mg of 4-(3-methoxybenzyloxy)-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and 3-methoxybenzylbromide in analogy to a procedure reported in Tetrahedron Lett. 38 (1997), 7887-7890) following the procedure given in Example 91. The compound was purified by column chromatography on silica gel eluting with DCM containing 0-2.5% of methanol followed by chromatography on prep. tlc-plates with DCM containing 5% of methanol. The resulting oil was dissolved in 10 ml of diethyl ether and treated with pentane. The precipitate was collected and dried to give 102 mg of 4-tert.-butyl-N-[6-(4-(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide as an almost white powder. LC-MS: tR=5.74 min, [M+1]+=696.40, [M−1]−=694.32.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 3-methylisothiazol-5-amine hydrochloride (50 mg, 0.332 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 5 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg, 0.219 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 384.2 (M+H); UV 209.0, 270.7, 321.3 nm; t 0.362 min.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)([CH3:31])=[CH2:30].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]([CH3:31])=[CH2:30])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: C=C(C)[Mg]Br
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (300 mg, 0.61 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 18.4 mL, 9.2 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (32 mg, 12%). LC/MS m/e calcd for C25H27NO4 (M+H)+: 406.50, observed: 406.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.20 Hz, 3 H) 1.53 (s, 3 H) 2.57-2.64 (m, 1 H) 2.64-2.71 (m, 1 H) 2.64-2.71 (m, 1 H) 2.71-2.78 (m, 1 H) 2.95-3.04 (m, 1 H) 3.15-3.22 (m, 1 H) 3.72 (s, 3 H) 3.81 (s, 3 H) 4.60 (s, 1 H) 4.72 (s, 1 H) 5.08 (s, 1 H) 6.04 (d, J=4.55 Hz, 2 H) 6.86 (s, 1 H) 6.89 (s, 1 H) 6.96 (s, 2 H).
Reaction SMILES: [OH-].[NH4+:2].[SH2]=N.[C:5]1([NH:11][C:12](C2C=CC=CC=2C(O)=O)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC(C)=O>[C:5]1([NH:11][C:12]([NH2:2])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)Nc1ccccc1

Procedure:
1 ml of an aqueous ammonium hydroxide solution (25%) was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml acetone, under stirring. The reaction mixture was stirred for 30 minutes at ambient temperature, then evaporated in vacuo and the residue was crystallized from water. 0.60 g phenylurea melting at 148°-150° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccnc1Br
Reaction time: 18 h

Procedure:
A solution of 2-bromo-3-hydroxy-pyridine (1 equiv., Aldrich Chemical Company) in THF is treated with NaH (1 equiv.) at 0° C. for 30 min. Methyl iodide (1 equiv.) is added and stirred for 18 h. The reaction mixture is evaporated, the residue is taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), dried over MgSO4 and evaporated to give 2-bromo-3-methoxy-pyridine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26]Cl>CS(C)=O.O>[CH:7]1([NH:13][CH2:26][CH2:25][O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2cc(OCCNC3CCCCC3)ccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.32 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloro ethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[2-(naphthalen-2-yloxy)-ethyl]amine, solid, m.p. 89° C., (yield 0.56 gm, 85.6%).