Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5 g), 3-chloroaniline (2.74 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for overnight. The precipitate was filtered, washed with dichloromethane and dried to give 5.2 g (74%) 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][NH:30][CH3:31])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CNCCCl
Product: CNCCn1cc(C(=O)N2CCC(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>Cl(O)(=O)(=O)=O>[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[C:21]1[N:1]=[C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:17]=1[NH:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Nc1ncccn1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(F)cc2Cl)nc2ncccn12

Procedure:
Compound (29) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml 2-chloro-4-fluorobenzaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%). Calculated mass 374.9; found mass 375.3 (ESI-MS)
Reaction SMILES: [O:1](C(O)C)C1C=CC=CC=1.[CH:11]1[CH:16]=[C:15]2[C:17]([NH:19][S:20][C:14]2=[CH:13][CH:12]=1)=O>>[S:20]1(=[O:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=2[CH:17]=[N:19]1
Reactant: O=c1[nH]sc2ccccc12
Reactant: CC(O)Oc1ccccc1
Product: O=S1N=Cc2ccccc21
Reaction time: 1 h

Procedure:
50% of 20% strength carbendasulf solution from Example 9 was combined with 10% of Proxel press paste (BIT) and 40% of phenoxyethanol and stirred for about 1 hour, giving a clear deep red solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ClCC1[C:24]([CH:40]2[CH2:42][CH2:41]2)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:24]([CH:40]3[CH2:41][CH2:42]3)=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:39])[F:38])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(-c2ccc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 142D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) was reacted with 3-chloromethyl-2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridine (example 143F]) to give the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH2:18]([SH:21])[CH2:19][CH3:20]>CN(C=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:21][CH2:18][CH2:19][CH3:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCCS
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1ccc(C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A solution of 4-chloro-3-nitro-toluene (25 g, 145 mmol) in anhydrous DMF (200 ml) was treated with K2CO3 (40.29 g, 291 mmol) and 1-propane thiol (12.2 g, 160 mmol). The reaction mixture was heated to 70° C. for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, diluted water and extracted with ethyl acetate (200 ml). The organic layer was washed with brine, dried over sodium sulphate and evaporated under reduced pressure, to give a crude which was purified by column chromatography (silica) using petroleum ether/ethyl acetate as eluent to afford the title compound (28 g, 91%) as a pale yellow solid.
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.[CH3:17][Si](I)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]([CH3:17])[C:7]1=[O:16]
Reactant: C[Si](C)(C)I
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1Cc2ccccc2C(N)C1=O
Temperature: 65 °C

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80° C. for 3 hrs and then cooled and poured into a seperatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([O:14][CH3:19])=[O:13])=[CH:5]2
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(O)ccc2cn1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.0 g, 5.2 mmol) in MeOH (50 mL) was added thionyl chloride (0.56 mL, 7.8 mmol) slowly. The reaction was heated at reflux for 18 h and then cooled to rt. The solvent was evaporated. The residue was redissolved in DCM and saturated NaHCO3 solution was added. The mixture was extracted with DCM (2×) and the combined organic solutions were dried over Na2SO4 and concentrated to give methyl 6-hydroxyisoquinoline-3-carboxylate as a white solid (0.72 g, 67%). LCMS: (FA) ES+ 208.2.
Reaction SMILES: [N:1]1([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([C:24]1[S:28][C:27]([S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[C:26](B(O)O)[CH:25]=1)[CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[N:1]1([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:26]3[CH:25]=[C:24]([CH2:20][CH:21]([CH3:22])[CH3:23])[S:28][C:27]=3[S:29]([NH:32][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cn1cnc2ccccc21)c1cccc(Br)c1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)Cc1cc(-c2cccc(C(=O)Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 2-benzoimidazol-1-yl-1-(3-bromophenyl)ethanone (42.7 mg, 0.136 mmol; see step (a)) in toluene (7 mL) and ethanol (1 mL) was added 5-isobutyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (73.5 mg, 0.230 mmol; see Example 1(c)), Pd(PPh3)4 (9.4 mg, 8.1 μmol) and Na2CO3 (271 μL, 0.542 mmol, 2.0 M aq), and the reaction mixture was stirred for 3 h at 80° C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The combined organic phase was dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound as a colourless syrup in 90% yield (62 mg, 0.122 mmol).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>CN1C(=O)CCC1.CCCCCCC.CCOC(C)=O>[NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cccc(Br)c31)CC(N)CC2
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cn1c2c(c3cccc(S(C)(=O)=O)c31)CC(N)CC2

Procedure:
A solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.238 mmol), cuprous iodide (204 mg, 1.073 mmol, 4.5 eq.) and sodium methanesulfinate (129 mg, 1.073 mmol, 4.5 eq.) in degassed NMP (5 ml) is heated under inert atmosphere at 140° C. overnight. Then, the mixture is diluted with heptane (5 ml) and AcOEt (5 ml) and filtered over a pad of silica gel with AcOEt as eluent. The solvent is removed in vaccuo and the residue dissolved in AcOEt and H2O. The phases are separated and the aq. phase is extracted twice with AcOEt. The combined org. phases are washed with brine and H2O, dried over Na2SO4 and concentrated in vacuuo to yield the corresponding ethyl (3-amino-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26].[C:28](O[BH3-])(=O)[CH3:29].[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:8]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:7]2[C:2]([N:1]([CH2:25][CH3:26])[CH2:28][CH3:29])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC=O
Reactant: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Reactant: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 3-{7-amino-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}propane-1,2-diol (Reference Example 87; 630 mg, 1.72 mmol) in methanol (17 mL) and acetic acid (0.34 mL) was added acetaldehyde (0.642 mL, 10.3 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium acetoxyborohydride (2.18 g, 10.3 mmol) at 0° C. After 1 hr, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (714 mg, 1.69 mmol, 98%) as a colorless solid.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>CC(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1ccccc1Cl
Solvent: CC(C)=O
Product: CC(=O)C(=NNc1ccccc1Cl)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(2-chlorophen yl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[3-chlorophenyl)hydrazono]-2-propanone.
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7]C(=O)CC1.C1([NH2:19])CC1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH2:7]1[C@@H:8]([NH2:19])[C@@H:3]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(CO)(c2ccccc2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-(hydroxymethyl)-4-phenylcyclohexanone (5.0 g, 24.5 mmol, 1.0 equiv.) in 1,2-dichloroethane (50 mL) was treated at 0° C. with cyclopropylamine (4.2 g, 74.0 mmol, 3.0 equiv.), 1 mL acetic acid and NaBH(OAc)3 (15.6 g, 74.0 mmol, 3.0 equiv.) successively. After being stirred at 25° C. for 12 h, the reaction mixture was diluted (EtOAc), washed (1×1 N aqueous NaOH and 2× brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 50% EtOAc/n-Hexane with 5% TEA) gave the trans amine isomer (the bottom spot on the TLC).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[CH2:6]([O:5][CH:4]([O:8][CH2:9][CH3:10])[CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:20])[CH2:22][CH2:23]1)[CH3:7]
Reactant: CCOC(CCCl)OCC
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Yield: 53 %

Procedure:
A mixture of 4.5 parts of 1-chloro-3,3-diethoxypropane, 12.15 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 10.6 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 9 parts (53%) of [1-(3,3-diethoxypropyl)-4-piperidinyl](4-fluorophenyl)methanone.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=[O:5])#[N:2].[H-].[Na+].C(O[CH:12]([O:16][CH2:17][CH3:18])N(C)C)C.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:35]([CH:37]([C:41]1CCCC(=O)[CH:42]=1)C(N)=O)#N>>[CH3:12][O:16][C:17]1[CH:18]=[C:42]([C:4]([CH2:3][C:1]#[N:2])=[O:5])[CH:41]=[CH:37][CH:35]=1
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Reactant: N#CCC(N)=O
Reactant: CCOC(OCC)N(C)C
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(C(=O)CC#N)c1

Procedure:
The novel intermediates of the present invention originate from a novel process which utilizes dihydro=resorcinol as the starting material. That substance thus is allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-1-one. Reaction with cyanoacetamide and sodium hydride results in α-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contacted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarboni=trile. Elimination of the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. Heating with an alkyl, trialkylsilyl or cycloalkyl halide produces the corresponding 6-alkoxy, 6-trialkylsilyloxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetra=lone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. The reaction of the keto group of the latter tetralone with vinyl magnesium chloride results in 7-aza-6-methoxy-1-vinyl-1-tetralol, which is contacted with a 2-(lower alkyl)cyclopentane-1,3-dione, such as 2-methylcyclopentane-1,3-dione, in the presence of a basic catalyst such as triethylamine to afford 5,6,7,8-tetrahydro-3-methoxy-8-[(2-methyl-1,3-dioxocylopent-2-yl)ethylidene]isoquinoline. Alternatively, the tetralol is converted to the iso-thiouronium salt, which is reacted with the dione to afford the latter product. Cyclization of the latter diketone, suitably in the presence of p-toluenesulfonic acid, results in dl-2-aza-3-methoxyestra-1,3,5(10), 8,14-pentaen-17-one. Catalytic hydrogenation, using a palladium-on-calcium carbonate catalyst effects saturation of the 14-double bond, thus producing dl-2-aza-3-methoxyestra-1,3,5(10),8-tetraen-17-one, while chemical reduction, for example with sodium borohydride, converts the 17-keto group, thus yielding dl-2-aza-3-methoxyestra-1,3,5(10),8,14-pentaen-17β-ol. The 14-double bond of the latter substance is catalytically reduced, using a palladium-on-calcium carbonate catalyst, to yield dl-2-aza-3-methoxy=estra-1,3,5(10),8-tetraen-17β-ol, which is allowed to react with sodium in liquid ammonia to afford dl-2 -aza-3-methoxyestra-1,3,5(10)-trien-17β-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([Cl:15])=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:16][CH:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>C(Cl)Cl>[ClH:15].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:13]([C:4]1[C:3]([O:2][CH3:1])=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=1)=[O:14])[CH2:18]2
Reactant: COc1cc2ccccc2cc1C(=O)Cl
Reactant: NC1CN2CCC1CC2
Solvent: ClCCl
Product: COc1cc2ccccc2cc1C(=O)NC1CN2CCC1CC2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A solution of 1.69 g (0.00768 mole) of 3-methoxy-2-naphthoic acid chloride in 15 ml of methylene chloride was added dropwise to a stirred solution of 0.97 g (0.00768 mole) of 3-aminoquinuclidine in 25 ml of methylene chloride in a closed system equipped with an oil bubbler. The reaction mixture was stirred overnight at ambient temperature, and then concentrated to give an off-white glassy solid. Two recrystallizations from methanol-isopropyl ether gave 1.95 g (73.4%) of the product as an off-white solid which was vacuum dried at ambient temperature, m.p. 248°-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([Na])=[N:23]1.O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: [Na]c1nc[nH]n1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Solvent: CCCO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mol) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane in 40 ml of n-propanol is added dropwise to a solution of 7.6 g (0.107 mol) of 1,2,4-triazolyl-sodium in 60 ml of n-propanol, at room temperature. The reaction mixture is stirred at the reflux temperature for a further 48 hours and is cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol are obtained. This is stirred with 20 ml of saturated hydrogen chloride/ether solution, at room temperature. The precipitate which separates out is filtered off under suction, rinsed with a small amount of ether and dried in vacuo at 40° C. 6.5 g (89% of theory, relative to base employed) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol hydrochloride of melting point 135° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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:1][C:2]1[N:3]=[C:4]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH:5]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[N:7]=1.[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[N:7]=[C:2]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[N:3]=1
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cc(N3CC4CCC(C3)O4)nc(Cl)n2)cc1
Product: Nc1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 120 °C
Yield: 16 %
Yield: 15 %

Procedure:
In a 2-5 mL microwave vial was placed 3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 100 mg, 0.384 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (84 mg, 0.384 mmol) in toluene (1.500 mL) and ethanol (1 mL) to give a light yellow solution. Na2CO3 (2M solution in water) (0.769 mL, 1.538 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (22.21 mg, 0.019 mmol) was added. The reaction was heated under microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3 (2×). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with 20-80% ethyl acetate in hexanes. Collected fractions were concentrated to give 4-[2-chloro-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-4-yl]-phenylamine (11, 19 mg, 16%) and 4-[4-chloro-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-yl]-phenylamine (12, 18 mg, 15%).