Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([N:23]([CH2:2][CH2:3][O:4][CH3:5])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COCCBr
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(c1ccc(C(=O)OC)c(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=1)=[O:8])[CH2:2]2.C1C=CN=CC=1.[FH:27].C(Cl)Cl>>[F:27][C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:8])[CH2:2]1
Reactant: O=C(OCc1ccc2ccccc2c1)N1CC2OC2C1
Reactant: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](O)[C@H](F)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 23.3 %

Procedure:
A plastic (HDPE) bottle was charged with naphthalen-2-ylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (945 mg, 3.509 mmol) and HF-pyridine (264 μL, 10.527 mmol) in DCM (17.55 ml, 3.509 mmol) and the reaction mixture was stirred for 36 hours at ambient temperature. The reaction was slowly quenched with aqueous saturated NaHCO3 and diluted with water and DCM. The reaction mixture was extracted with DCM, and the combined organics layers were dried over Na2SO4 and concentrated to give the product as an oil (237 mg, 23.3% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:14])[CH3:13])[CH:5]=[C:6](F)[C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].CS(C)=[O:19].Cl>O>[CH3:13][N:12]([CH3:14])[C:4]1[CH:3]=[C:2]([F:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:19])[CH:5]=1
Reactant: CN(C)c1cc(F)c([N+](=O)[O-])c(F)c1
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1cc(O)c([N+](=O)[O-])c(F)c1
Reaction time: 2 h

Procedure:
(3,5-Difluoro-4-nitro-phenyl)-dimethyl-amine (0.630 g, 3.12 mmol) and 19.1 M of Sodium hydroxide in Water (0.400 mL) in Water (4 mL) and Dimethyl sulfoxide (8 mL) was heated to 70° C. Additional DMSO (8 mL) was added to solubilize the mixture. After 2 h, the solution was cooled then rendered acidic with 12.0 M of Hydrogen Chloride in Water (0.80 mL). The yellow precipitate was collected, using water to aid in the transfer and to rinse the solids. 5-Dimethylamino-3-fluoro-2-nitro-phenol was isolated as yellow solids (598 mg, 96%). 1H-NMR (DMSO): 11.10 (s, 1H), 6.29 (d, 1H, J=15.6 Hz), 6.02 (s, 1H), 3.01 (s, 6H); 19F−NMR (DMSO): −118.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([NH:5][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(N)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 15.2 g (125 mmole) of 3,5-dimethylaniline in 60 mL of toluene was added 15 g (146 mmole) of acetic anhydride, whereupon the internal temperature rose to 75° C. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in 150 mL of hot ethyl acetate and the solution allowed to stand for 16 hours. The resulting mixture was cooled at 5° C. for 3 hours and the solid collected by filtration to give 18.43 g (90%) of off white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]Cl)=[CH:7][C:6]=2[CH:12]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[N:13]([CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][C:6]=2[CH:7]=1)=[N+:14]=[N-:15]
Reactant: ClCc1cc2cc(Cl)ccc2o1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cc(Cl)ccc2o1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 5-chloro-2-(chloromethyl)-1-benzofuran (500 mg, 2.49 mmol) in N,N-dimethylformamide (10 ml) was added NaN3 (320 mg, 4.92 mmol) and the contents were stirred overnight at 70° C. The resulting solution was diluted with saturated aqueous sodium bicarbonate (150 ml) and extracted with dichloromethane (3×70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether to afford 2-(azidomethyl)-5-chloro-1-benzofuran as light brown oil (500 mg, 97%). 1H NMR (300 MHz, CDCl3): δ 7.54 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.66 (s, 1H), 4.50 (s, 2H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([NH:9][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: CCCCCCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 26 was repeated, but using 2.7 g of octylamine, 4.0 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine and 15 ml of dimethylformamide, giving the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1([CH2:13][OH:14])[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Br:1][C:2]1([CH:13]=[O:14])[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)[C@H]1[C@H](C(=O)OC)C1(Br)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@H](C(=O)OC)C1(Br)C=O
Reaction time: 16 h
Yield: 69.3 %

Procedure:
To a stirred solution of (1R,2R)-3-bromo-1,2-dicarbomethoxy-3-hydroxymethyl-cyclopropane (2.8 g, 10.5 mmol) in dichloromethane (120 ml) was added pyridinium chlorochromate (3.35 g, 15.7 mmol) and stirring continued over a period of 16 hours. Diethyl ether (120 ml) was added to the reaction mixture, which was then filtered with the aid of a Whatman glass microfibre filter and evaporated. Column chromatography of the crude product (diethyl ether/hexane 1:1) yielded (1R,2R)-3-bromo-1,2-dicarbomethoxy-3-formyl-cyclopropane (1.93 g, 69%) as a white solid. mp 52° C.; [α]20D=+108° (c=0.25 in MeOH): 1H NMR (CDCl3): d 3.16 (d, J=6.5 Hz, 1H), 3.27 (d, J=6.5 Hz, 1H), 3.76 (s, 3H), 3.83 (s. 3H), 9.26 (s, 1H). MS (EI) m/z 265, 267 [M+H+ ], 233, 235 (24) [M+ --OMe], 204, 206 (24), 176, 178 (44), 153 (100), 125 (95), 59 (69).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[O:1]=[S:2]1(=[O:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:15]/[C:16](/[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:34]\[OH:35])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCS(=O)(=O)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCS(=O)(=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-[4-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a light yellow foam, MS (ESI+): m/z=464.2 ([M+H]+).
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH2:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH2:4]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:1][CH3:2])[C:15]#[N:16])=[CH:12][CH:13]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)Cc1ccc(CC#N)cc1
Reactant: CCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CCC(C#N)c1ccc(CC(C)C)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
550 g of ethyl bromide are added drop-wise to 470 g of 4-isobutylphenyl acetonitrile, 1550 g of a 50% solution of sodium hydroxide and 11.4 g of triethylbenzyl ammonium chloride. The addition is complete within 2 hours. During this addition, the temperature must be controlled such that it does not exceed 40° C. The mixture is agitated for 10 hours at 40° C. After cooling of the mixture, the alkaline phase is discarded and the organic layer is washed with water until neutral. Fractionation yields 536 g of crude 2-(4-isobutylphenyl)butyronitrile.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=3[N:15]=[N:14][C:13]2=[O:24])[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:41]2[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]4[C:17]5[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=5[N:15]=[N:14][C:13]4=[O:24])[CH2:6][CH2:5]3)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2nnc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2nnc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Yield: 51 %

Procedure:
A mixture of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)-1,2,4-benzotriazin-3(4H)-one dihydrochloride (42 mg, 0.112 mmol) in chloroform (2 ml) and MeOH (0.1 ml) was treated with triethylamine (50 μl, 0.358 mmol) and stirred for 0.25 h before addition of 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (18 mg, 0.112 mmol). The reaction was stirred for 0.5 h before addition of NaBH(OAc)3 (71 mg, 0.336 mmol). The reaction was stirred for 1 h before addition of sat. aq NaHCO3 (10 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (26 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[OH-].[Na+]>CC(O)C>[Cl:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 850.8 %

Procedure:
Method A To a solution of 4-chlorobenzyl cyanide (5.62 g, 4.00 mmol) and 3-chloro-benzaldehyde (Aldrich) (6.06 g, 4.00 mmol) in iPrOH (250 mL) was added 4 N NaOH (5 mL) dropwise at rt and the reaction mixture was stirred at rt for 10 min to give a white suspension. The solid was filtered and washed with water and iPrOH and then dried overnight in vacuum to give (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (9.33 g, 85.1%) as a white powder which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[CH:4]=[O:5].[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[NH:20][N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O.[Cu]I>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:6]1[CH:7]=[CH:8][N:9]=[C:2]([Cl:1])[C:3]=1[CH:4]=[O:5])[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3ccnc(Cl)c3C=O)ncc2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
In a 50 mL round-bottomed flask, 2-chloro-4-iodonicotinaldehyde (389 mg, 1.45 mmol, Eq: 1.6), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (200 mg, 908 μmol, Eq: 1.00) and potassium carbonate (251 mg, 1.82 mmol, Eq: 2) were combined with DMSO (8 ml) to give a yellow solution. The solution was degassed for 5 min with argon. Copper(I) iodide (173 mg, 908 μmol, Eq: 1.00) was added. The reaction mixture was heated to 110° C. and stirred for 2 h and the reaction was allowed to cool to room temperature. The reaction was diluted with 1:1 H2O/sat. NH4Cl (80 mL) and the resulting solid collected by filtration. The solid was washed several times with 1:1 H2O/sat. NH4Cl, then water (2×) and then EtOAc:hexanes (3:1, 2×). A lot of color in the organic phase. A brown solid remained. Solid was washed with EtOAc and then CH2Cl2 several times. The combined organic extracts were washed with water, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 40 g, 5% to 30% EtOAc in hexanes) to afford the desired product (170 mg) as a white solid. (M+H)+=360 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 7.40-7.65 (m, 3 H) 8.24 (d, J=2.64 Hz, 1 H) 8.66 (d, J=5.29 Hz, 1 H) 10.32 (s, 1 H).
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[CH:25]=[CH:24][C:6]([NH:7][C:8]([C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=2)[NH:13][C:14]2[CH:19]=[CH:18][N+](C)=CC=2)=[O:9])=[CH:5][CH:4]=1.O.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl>CCO.CCOC(C)=O.CO.CCCCO>[Cl-:27].[Cl-:1].[CH3:8][N:7]1[CH:6]=[CH:5][CH2+:18]=[CH:19][CH:14]1[NH:13][C:12]1[CH:11]=[C:10]([CH:23]=[CH:22][CH:21]=1)[C:8]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH+:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1)=[O:9]
Reactant: Clc1ccnc2ccccc12
Reactant: C[n+]1ccc(Nc2cccc(C(=O)Nc3ccc(N)cc3)c2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CN1C=C[CH2+]=CC1Nc1cccc(C(=O)Nc2ccc(Nc3cc[nH+]c4ccccc34)cc2)c1
Temperature: 25 °C

Procedure:
Compound C6 (100 mg, 0.28 mmol) was dissolved in EtOH (10 mL) and H2O (5 mL) by heating. 4-Chloroquinoline (60 mg, 0.36 mmol) and 3 drops of c. HCl were added, and the mixture refluxed for 18 h (until TLC with the top phase of 5:4:1 mixture of n-BuOH:H2O:CH3CO2H showed complete consumption of starting amine). The reaction mixture was then diluted with EtOAc, boiled for a few minutes and then allowed to cool to room temperature. The resulting precipitate was filtered and crystallized from MeOH/EtOAc to give Cpd. C (64 mg, 63%); mp (MeOH, EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 14.49 (br, 1H, N+H), 11.01 (s, 1H, NH), 11.78 (br, 1H, NH), 10.64 (s, 1H, NH), 8.77 (d, J=8.5 Hz, 1H, ArH), 8.57 (d, J=6.5 Hz, 1H, ArH), 8.32 (d, J=7.5 Hz, 2H, ArH), 8.06-7.92 (m, 6H, ArH), 7.53 (t, J=7.7 Hz, 1H, ArH), 7.70-7.65 (m, 1H, ArH), 7.48 (d, J=8.8 Hz, 2H, ArH), 7.29 (d, J=7.5 Hz, 2H, ArH), 6.79 (d, J=6.8 Hz, 1H, ArH), 3.98 (s, 3H, N+CH3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:7].[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH3:17])=[CH:11][CH:12]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(CCCCCl)NCc1ccc(Cl)cc1
Product: Cc1nccn1CCCCC(=O)NCc1ccc(Cl)cc1
Yield: 53.7 %

Procedure:
In a similar manner to Example 70, 5-chloro-N-(4-chlorobenzyl)valeramide (10.3 g, prepared from 4-chlorobenzylamine and 5-chlorovaleryl chloride) and 2-methylimidazole (6.5 g) were reacted together to give N-(4-chlorobenzyl)-5-(2-methylimidazol-1-yl) valeramide, (6.5 g) , m.p. 72°-75° C. which was reduced with borane/THF (86 ml, 1M) to give N-(4-chlorobenzyl)-5-(2-methylimidazol-1-yl)pentylamine, b.p. 170°-185° C. (0.1 mmHg).
Reaction SMILES: C(O[C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:26])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([CH:15]=[C:16]([O:24][CH3:25])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[I-].[CH3:28][S+](C)(C)=O.[OH-].[K+]>O>[CH2:28]1[C@@H:6]2[C:7](=[O:26])[C@:8]3([CH2:23][CH2:22][C@H:21]4[C@@H:11]([CH2:12][CH:13]=[C:14]5[C@:19]4([CH3:20])[CH2:18][CH2:17][C:16]([O:24][CH3:25])=[CH:15]5)[C@@H:10]3[C@H:5]12)[CH3:9]
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 6 h

Procedure:
The 15α-acetoxy-3-methoxy-androsta-3,5-diene-17-one of the general formula (V) is treated with a reagent prepared in situ from trimethylsulfoxonium iodide and potassium hydroxide in a solvent, the reaction mixture is stirred for 6 hours then added to water. The precipitate is filtered off, washed to remove the mother liquor and dried. Finally the 15β,16β-methylene-3-methoxy-androsta-3,5-diene-17-one obtained (a compound of the general formula (VII)) is crystallized from methanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][N:3]=1.[CH3:14][N:15](C)C>C1(C)C=CC=CC=1>[C:14]([C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][N:3]=1)#[N:15]
Reactant: FC(F)(F)COc1ccnc(Cl)n1
Reactant: CN(C)C
Solvent: Cc1ccccc1
Product: N#Cc1nccc(OCC(F)(F)F)n1
Reaction time: 16 h
Yield: 77 %

Procedure:
The 2-chloro-4-(2,2,2-trifluoroethoxy)-pyrimidine (142 g) in toluene (330 ml) was added to trimethylamine (140 ml of a 45% aqueous solution) at 0° C. After stirring for 16 hours the organic phase was separated off. The aqueous phase was added to toluene (330 ml) then a solution potassium cyanide (44 g in 170 ml water) was added at 0° C. The reaction mixture was stirred for a further 16 hours and then the organic phase was separated, the aqueous was extracted with ether (2×200 ml) and the combined organic extracts were dried and concentrated to give 2-cyano-4-(2,2,2-trifluoroethoxy)-pyrimidine (73.5 g, 77% yield) as a yellow oil; 1H NMR (270 MHz): δ4.85(2H,q), 7.10(1H,d), 8.64(1H,d) ppm.
Reaction SMILES: C(OC(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:31][CH:30]=1)[CH3:28].[C:43]([O:46]CC)(=[O:45])[CH3:44].[OH-].[K+]>CO>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[C:32]1[CH:33]=[CH:34][C:29]([CH:27]([CH3:28])[CH2:44][C:43]([OH:46])=[O:45])=[CH:30][CH:31]=1
Reactant: CCOC(C)=O
Reactant: CC(Br)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
69.7 g. of triphenylphosphoranylideneacetic acid ethyl ester and 29.7 g. of 4-(1-bromoethyl)-2',4'-difluorobiphenyl in 300 ml. of absolute ethyl acetate are heated under reflux for 54 hours. The precipitate is filtered off and the filtrate is evaporated. Crude [1-(2',4'-difluoro-4-biphenylyl)ethyl]triphenylphophoranylideneacetic acid ethyl ethyl ester thus obtained is dissolved in 500 ml. of methanol to which 150 ml. of 20% potassium hydroxide solution are added and the mixture is heated under reflux for one hour. The methanol is distilled off, water is added and the reaction mixture is washed with ether and acidified with hydrochloric acid to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]1[C:38]([Cl:39])=[CH:37][C:31]2[C:32](=O)O[C:34](=O)[C:30]=2[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[C:30]2[C:31](=[CH:37][C:38]=1[Cl:39])[CH2:32][N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[CH2:34]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6cc(Cl)c(Cl)cc6C5)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5,6-dichloro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.Cl.[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([F:35])[CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH2:9][C:6]3[C:5]([CH2:11][OH:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=3[OH:8])=[C:30]([F:35])[CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Agent: Cl
Product: Cc1ncc(CO)c(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2F)c1O

Procedure:
The reductive amination of pyridoxal hydrochloride (436.4 mg, 2.143 mmol) and 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (760 mg, 2.357 mmol), following the procedure described in Example 7, gave 3′-fluoro-4′-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (9).