Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:29][C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:30][C:25]=2[N:26]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3oc(C)nc3c2)cc1
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (93 mg, 0.43 mmol) in dichloromethane (2 mL) was added pyridine (80 μL, 1.0 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-2-methylbenzoxazole (60 mg, 0.40 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink oil (112 mg, 85%), single spot at Rf 0.53 (1:1 hexane:ethyl acetate). HPLC purity 99+% (tR 2.38 min in 10% water-acetonitrile) 1H NMR (CDCl3): δ 7.64 (2H, dt, J=8.1, 1.8 Hz), 7.31 (2H, m), 7.18 (2H, d, J=8.4 Hz), 7.06 (1H, dd, J=8.6, 2.4 Hz), 2.59 (5H, m), 1.58 (2H, sextet, J=7.3 Hz), 0.89 (3H, t, J=7.3 Hz). LCMS: 329.15 (M−). FAB-MS (MH+, C17H18N2O3S): calcd 331.1116, found 331.1118.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nccc(-c2cccc(CNCc3cccnc3)c2)n1
Product: CS(=O)(=O)N(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 12 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([CH3:11])[C:6]=2[CH:12]=1.[H][H]>O1CCOCC1.[Pd]>[NH2:13][C:3]1[C:2]([Cl:1])=[CH:12][C:6]2[CH:7]([CH3:11])[C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: CC1C(=O)Oc2cc(N(Cc3ccccc3)Cc3ccccc3)c(Cl)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC1C(=O)Oc2cc(N)c(Cl)cc21

Procedure:
A solution of 21.8 g (0.058 mole) of 5-chloro-6-dibenzylamino-3-methylbenzofuran-2(3H)-one in 220 ml of dioxane is reduced with 2.0 g of palladium-on-carbon (5% strength) at room temperature with hydrogen without superatmospheric pressure. After absorption of the theoretical amount of hydrogen the catalyst is removed by filtration and the dioxane is evaporated off in vacuo. 20 ml of cold methanol are added to the residue and the precipitate is filtered off. 6-amino-5-chloro-3-methylbenzofuran-2(3H)-one is obtained in the form of colourless crystals having a melting point of 139°-140°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[CH:18][N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[Cl:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]([CH:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(Cl)ncn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(Cc1ccccc1)c1cc(Cl)ncn1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
[1-(6-Chloro-pyrimidin-4-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: A white suspension of 10A (1.39 g, 4.41 mmol) in phosphorus oxychloride (20.54 mL, 220 mmol) was warmed to 50° C. to give a clear, pale yellow solution. After 3 h, the orange-brown solution was cooled to rt and concentrated in vacuo to give an orange-brown residue. The residue was dissolved in CH2Cl2 and concentrated (2×). The residue was dissolved in CH2Cl2 and sat. NaHCO3 was added. The mixture was stirred vigorously for 10-15 min. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 0.990 g of 1-(6-chloropyrimidin-4-yl)-2-phenylethanamine as a thick, viscous orange-brown residue. MS 234.0 (M+H)+; 236 (M+2+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:30][CH:29]([CH2:31][C:32](OC)=[O:33])[CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][CH:29]5[CH2:30][O:27][CH2:28]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: COC(=O)CC1COC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (66 mg, 62%), MS (ISP) m/z=427.4 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 81 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and methyl 2-(oxetan-3-yl)acetate.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:10][NH:11][C:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20]I)[N:19]=1)=[O:13].[CH3:26][C:27]1[C:31]([S:32]([O-:34])=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.[Na+]>O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:10][NH:11][C:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:32]([C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[CH3:35])(=[O:34])=[O:33])[N:19]=1)=[O:13]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: Cc1noc(C)c1S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1S(=O)(=O)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A DMF (0.30 mL) solution of Intermediate 6: 1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (45 mg, 0.10 mmol) and sodium 3,5-dimethylisoxazole-4-sulfinate (56 mg, 0.2 mmol, ˜60% pure) was stirred for an hour. The mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried and evaporated to a residue that was purified by chromatography (silica gel) to afford the title compound. 1H NMR (400 MHz, CDCl3): 9.80 (1H, br), 7.39 (m, 2H), 7.15 (dd, 1H), 6.77 (s, 1H), 4.42 (d, 2H), 4.37 (s, 2H), 2.37 (s, 3H), 2.22 (s, 3H). MS (ES+): M/Z 475 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(C2CCCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 312.2 %

Procedure:
3-Amino-1-N-Boc-piperidine (2.5 g, 12.5 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 34 mL, 11 3 mmol) and heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (20 mL) and potassium carbonate powder (2.2 g, 15.8 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (100 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×, 50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 4.93 g (82% yield) of ethyl 1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:22]=[N+:23]=[N-:24])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[NH:24][N:23]=[N:22][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCc1cccc(OCc2ccccc2)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: c1ccc(COc2cccc(Cc3nnn[nH]3)c2)cc1
Temperature: 110 °C

Procedure:
To a stirring solution of 3-benzyloxyphenylacetonitrile (2.0 g, 8.95 mmol) in toluene (17 ml) was added trimethylsilylazide (2.37 g, 17.9 mmol) and di-n-butyltin oxide (0.22 g, 0.9 mmol). The mixture was heated at 110° C. for 48 h, and was concentrated. The reaction mixture was dissolved in ethyl acetate (100 ml) and washed two times with 10% aqueous sodium bicarbonate. The basic extracts were acidified to pH<2 with conc. HCl, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product (2.0 g, 89%) was used in the next step without further purification. MS (ESI) 267.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]2[CH2:18][CH2:17]2)[CH:9]=[C:10]([F:15])[C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:16]2[CH2:17][CH2:18]2)[CH:9]=[C:10]([F:15])[CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)=CC(c1ccc(Cl)cc1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCC(F)=CC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
Methyl 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enoate prepared as described in Example 1 (0.91 g) in dry diethyl ether (20 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.34 g) in dry diethyl ether (25 ml) at 0° C. Stirring was continued during 40 minutes, while the mixture warmed to room temperature. Water (4 ml) was added, and the mixture was extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (3×10 ml), dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel using diethyl ether/hexane (2:3) to yield 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enol (0.61 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]([CH3:15])([CH:13]=[CH2:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:11][C:10](=[O:12])[CH2:9][C:8]([CH2:7][C:6]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:15])[CH:13]=[CH2:14])[CH3:20]
Reactant: CCO
Reactant: C=CC(C)(CC(=O)O)Cc1ccc(OC)cc1
Agent: Cl
Product: C=CC(C)(CC(=O)OCC)Cc1ccc(OC)cc1

Procedure:
A solution of product prepared in STEP 3 (5.6 g), saturated hydrochloric acid/ethanol (70 ml) was stirred at room temperature overnight. Solvent was removed. The crude product was purified on a silica gel column, eluting with 0.5% ethyl acetate/hexane to afford colorless oil (3.3 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[CH3:19][S:20]([O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:2]([CH3:18])([CH3:1])[C:6]=2[CH:7]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)c2cc(O)ccc2OC1N1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1N1CCCCC1
Temperature: 10 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a stirred solution of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-piperidino-benzofuran (640 parts) in dry pyridine (1000 parts) at 5°-10° C. was added methanesulphonyl chloride (370 parts) over 1 hour. The mixture was stirred for a further 5 hours at about 10° C., then poured into water. The precipitated gum was washed with water (3 × 200 parts) by decantation, then triturated with ethanol (500 parts) when it set to a crystalline moss which was broken up, filtered, and the residue of crude ester was washed with aqueous ethanol (2:1) and sucked dry. Drying at 35° C. in vacuo over phosphoric oxide gave 2,3-dihydro-3,3-dimethyl-2-piperidinobenzofuran-5-yl methanesulphonate (660 parts, 78%) m.p. 97°-8° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.C(N(CC)CC)C.[CH2:32](Br)[CH:33]=[CH2:34]>CN(C)C=O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:34][CH:33]=[CH2:32])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: C=CCBr
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
To a stirred solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.5 g; 1.37 mmol), prepared as in Example 10, and triethylamine (0.3 g; 3.0 mmol) in N,N-dimethylformamide (10 mL), was added allyl bromide (0.17 g; 1.4 mmol) in N,N-dimethylformamide (approximately 2 mL). The reaction mixture was stirred for 1.5 hours and the solvent removed. The residue was stirred with ammonium hydroxide and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2×50 mL) and purification of the combined methylene chloride layers by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2,3-dihydro-2-(1-prop-2-enylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.1 g; 0.27 mmol), m.p. 279°-281° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=O)[CH2:12][CH2:11]2)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1.Cl.[O:27]([NH2:29])[CH3:28]>C(O)C>[CH3:28][O:27][N:29]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:3]2[C:2]([Br:1])=[CH:6][N:5]([CH3:7])[N:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CON
Reactant: Cn1cc(Br)c(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)n1
Agent: Cl
Solvent: CCO
Product: CON=C(CN1CCN(C(=O)c2nn(C)cc2Br)CC1)c1ccc(F)cc1
Temperature: 90 °C
Yield: 23.8 %

Procedure:
2-(4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)ethanone (100 mg, 0.24 mmol) and methoxylamine hydrochloride (25 mg, 0.31 mmol) were taken up in ethanol (10 mL) in a round-bottom flask and heated to reflux at 90° C. for 21 h. The solvent was removed under reduced pressure and saturated aqueous NaHCO3 (1.5 mL) was added. The mixture was extracted three times with DCM and the organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative TLC plate (Rf=0.44, 60% EtOAc/Hexane, UV 254 nm) and dried to afford the title compound (25 mg) as a free base. 1H NMR (Acetonitrile-d3, 400 MHz) δ 2.42-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.35-3.42 (m, 2H), 3.37 (s, 2H), 3.57-3.63 (m, 2H), 3.80 (s, 3H), 3.84 (s, 3H), 7.14 (t, J=8.84 Hz, 2H), 7.60 (dd, J=5.31, 8.84 Hz, 2H), 7.61 (s, 1H). Exact mass calculated for C18H21BrFN5O2: 437.1. Found: LCMS m/z (%)=438.3 (M+H+79Br, 100%), 440.3 (M+H+81Br, 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5]([F:10])[CH2:4]1.[CH:18]1[CH:19]=[CH:20][C:21]2[NH:26][CH:25]=[C:24]([CH2:27][CH2:28]O)[C:22]=2[CH:23]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[OH-].[Na+]>ClCCl>[F:10][CH:5]1[C:6]2([C:25]3[NH:26][C:21]4[C:22]([C:24]=3[CH2:27][CH2:28][O:9]2)=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH2:7][CH2:8][C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([N:2]([CH3:17])[CH3:1])[CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(F)C1
Reactant: OCCc1c[nH]c2ccccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(OCCc3c2[nH]c2ccccc32)C(F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(±)-4-dimethylamino-2-fluoro-4-phenylcyclohexanone (1.61 g, 6.83 mmol, mixture of both diastereoisomers, mainly polar diastereoisomer) together with tryptophol (1.10 g, 6.83 mmol) was dissolved in absolute dichloromethane (75 ml) at 0° C. (inside temperature). Trimethylsilyl triflate (1.67 g, 7.51 mmol, 1.36 ml, 1.225 g/ml) was then added quickly in drops to absolute dichloromethane (10 ml). The reaction mixture immediately changed colour from yellow to red-brown. The reaction mixture was stirred for 5 h at room temperature and became cloudy during this. 5N sodium hydroxide solution (100 ml) was added to the reaction mixture and stirred for 10 min. After phase separation the aqueous phase was extracted with dichloromethane (4×50 ml). The combined organic phases were dried over sodium sulphate, filtered and then completely freed of volatile constituents in a vacuum. An attempt was made to separate the residue by chromatography [silica gel (150 g), chloroform/ethanol 50:1 (500 ml), 19:1 (500 ml), 9:1 (1000 ml), 1:1 (500 ml), methanol (1000 ml)]. 467 mg (1.23 mmol, 18%, mp 259-263° C.) of a more non-polar diastereomer, 506 mg (1.34 mmol, 20%, mp 217-222° C.) of a diastereomer of average polarity and 168 mg (0.44 mmol, 6%, mp 245-247° C.) of a more polar diastereoisomer were isolated. The individual fractions were recrystallised from methanol.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([CH3:24])=[N:6][C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-methyl-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.077 mmol), glycine (770 mg, 10.3 mmol) and NaOMe solution (15 mL, 7.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (5-70% EtOAc/hexanes+2% AcOH) to give 21 mg of the title compound as a pale yellow solid. MS: (+) m/z 367.98 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[S:18][C:19]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(#N)C.Cl>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[S:18][C:19]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc2ccccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(C(=O)O)sc3ccccc23)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 88 (0.120 g; 0.31 mmol) in methanol (2 mL) was added aqueous sodium hydroxide (1 mL; 2 mmol; 2N). Acetonitrile (2 mL) was added to aid in solubility, and the resulting mixture was stirred overnight. The reaction mixture was acidified with aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, decanted, and concentrated under reduced pressure. Trituration of the crude product from hexanes and dichloromethane yielded the desired product as a pink solid (121 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
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: CCO
Product: Cc1ccc(-c2cc(N)ccc2C)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask containing 5-amino-2-methyl-phenylboronic acid pinacol ester (348 mg, 1.5 mmol), 2-chloro-5-methylpyridine (381 mg, 3 mmol), Pd(PPh3)4 (192 mg, 0.15 mmol) is added toluene (12 ml), EtOH (3 ml) and 2M aqueous Na2CO3 solution (3 ml). The flask is purged with argon and sealed. The mixture is stirred at 90° C. for 18 hours, cooled to room temperature and then water (20 ml) and ethyl acetate (20 ml) are added. The organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The residue is purified by silica gel flash chromatography, eluted with 2% methanol in dichloromethane to afford 4-Methyl-3-(5-methylpyridin-2-yl)aniline as a brown oil. LC-MS m/z: 199.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(C)ccc23)cc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(C)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-methoxyphenyl)-7-methylphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.