Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)CCC.O>CN(C=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.[Cu]I>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(O)(c1cccc(-c2ccccn2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
1-(3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.15 g) and a solution of tri-n-butyl(2-pyridyl)tin (1.01 g) in DMF (10 ml) was deaerated and tetrakis(triphenylphosphine)palladium(0) (73.1 mg) was added. The mixture was stirred under an argon atmosphere at 80° C. for 5 h and copper(I) iodide (20.1 mg) and tetrakis(triphenylphosphine)palladium(0) (48.7 mg) were added. The mixture was stirred at 100° C. for 18 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with 5% aqueous ethylenediamine solution, water (twice) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=3:1→2:1). Recrystallization from ethyl acetate-hexane gave the title compound (577 mg, 51%) as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][OH:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: OCC1CCO1
Product: N#Cc1cnc(N)cc1OCC1CCO1

Procedure:
From intermediate 16 and oxetan-2-ylmethanol, reacted in an analogous manner to the preparation of intermediate 34. (UPLC-MS 3) tR 0.45 min; ESI-MS 206.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
With vigorous stirring, 9.15 g (0.065 mole) of 2-fluoro-4-methoxyaniline (Example 3, Step B) was added to 60 mL of concentrated hydrochloric acid that had been cooled to -10° C. A solution of 4.83 g (0.070 mole) of sodium nitrite in 30 mL of water was slowly added dropwise, while the temperature was kept at or below -10° C. Upon completion of addition, the reaction mixture was stirred at -10° C. for one hour, after which 33.85 (0.150 mole) of tin(II) chloride dihydrate in 50 mL of concentrated hydrochloric acid Was added slowly, dropwise, while the temperature was kept below -5° C. After the reaction mixture had stirred for one hour as it warmed to ambient temperature, the crude product was filtered from the mixture and dissolved in 250 mL of water. This solution was made basic with 4N sodium hydroxide and extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was placed on a silica gel column and eluted with methylene chloride to remove colored impurities and then with ethyl acetate to obtain the desired product. The solvent was evaporated under reduced pressure to yield 6.30 g of 2-fluoro-4-methoxyphenylhydrazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:3](=[CH2:2])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:15][CH:16]=1
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1c2ccccc2C(=O)C1c1ccncc1
Temperature: 25 °C

Procedure:
##STR5## 13.2 g of indanone, 15 g of pyridine-4-aldehyde and 19 g of p-toluenesulphonic acid were heated to boiling under reflux in a water separator for 5 h in 250 ml of toluene. The resulting precipitate was filtered off with suction after cooling and stirred at room temperature for 30 rain in 10% sodium carbonate solution. The resulting, pale-yellow precipitate was filtered off with suction, washed with water and dried in air. Yield: 19.3 g (87%)
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:25])[CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)C>C1COCC1.CO.O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:25])=[O:5])=[O:24])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
LiOH (1.32 g, 31.5 mmol) was added to a stirred solution of (4-benzyloxy-benzoylamino)-acetic acid ethyl ester (2.47 g, 7.8 mmol) in THF:MeOH:H2O (2:2:1, 50 mL). The resulting mixture was stirred at room temperature overnight. The MeOH and THF were evaporated and the residue was diluted with water (20 mL) and acidified with 10% HCl solution. The resulting precipitate was washed with water followed by hexane and dried to afford 2.03 g (90.6 yield) of (4-benzyloxy-benzoylamino)-acetic acid. 1H NMR: (DMSO) δ 7.9 (d, 2H), 7.8 (s, 1H), 7.5 (m, 5H), 7.1 (d, 2H), 5.2 (s, 2H), 3.6 (d, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[C:21](Cl)(=[O:29])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:21](=[O:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:1][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(CO)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a mixture of 2-hydroxy-4′-trifluoromethyl acetophenone (24.0 g), pyridine (10.3 g) and tetrahydrofuran (200 ml) was added dropwise phenyl chlorocarbonate (20.4 g) under ice-cooling, which was stirred at room temperature for 1 hour. The reaction mixture was concentrated, which was poured into water (500 ml), and extracted with ethyl acetate (150 ml×2). The organic layer was washed with water and then a saturated aqueous solution of sodium chloride, which was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to crystallization by addition of isopropyl ether (100 ml) to give crystals of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.9 g, 53%). Melting point 134-135° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:28]1[C:29]2[CH:38]=[CH:37][O:36][C:30]=2[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[CH:8][C:7]=2[C:28]2[C:29]3[CH:38]=[CH:37][O:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:2][CH2:3]1
Reactant: CCS(=O)(=O)Nc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)c2ccoc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3occc23)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 15.8 %

Procedure:
A mixture of N-[4-(cyclopropylmethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide (138 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75 mg, 0.33 mmol), K3PO4 (175 mg, 0.83 mmol), Pd(dppf)Cl2 (24 mg, 10%) in dioxane (2.2 mL) and H2O (200 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70° C. for 4 h. After the reaction mixture was filtered through a short plug of celite, the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (21 mg, 16%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.15-0.28 (m, 2H) 0.35-0.52 (m, 2H) 0.95-1.13 (m, 1H) 1.14-1.26 (m, 3H) 2.98-3.09 (m, 2H) 3.57-3.65 (m, 3H) 3.77-3.87 (m, 2H) 7.04-7.22 (m, 3H) 7.55-7.64 (m, 1H) 8.05-8.17 (m, 1H) 9.49-9.57 (m, 1H). LCMS (M+H)+=403.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[OH:14][C:15]1([CH3:31])[CH:20]2[CH2:21][NH:22][CH2:23][CH:16]1[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2>C(#N)C.O>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:22]2[CH2:21][CH:20]3[C:15]([OH:14])([CH3:31])[CH:16]([CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[CH2:23]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)C2(C)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)C2(C)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
4-[(2S)-Oxiranylmethoxy]benzonitrile (from step (v) above, 247 mg, 1.4 mmol) was added to a stirred solution of tert-butyl 9-hydroxy-9-methyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above, 328 mg, 1.28 mmol) in acetonitrile:water (4:1). The reaction was heated to 60° C. for 12 h, after which stirring was continued at rt for a further 48 h.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:32])[C:10]2[O:16][C:15]3[C:17]([Cl:28])=[CH:18][C:19]([N:21]([CH2:25][CH2:26][Cl:27])[CH2:22][CH2:23][Cl:24])=[CH:20][C:14]=3[CH2:13][S:12](=[O:30])(=[O:29])[C:11]=2[CH:31]=1)=[O:6]>O1CCCC1>[Cl:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][Cl:27])[C:19]1[CH:18]=[C:17]([Cl:28])[C:15]2[O:16][C:10]3[C:9]([CH3:32])=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:31][C:11]=3[S:12](=[O:29])(=[O:30])[CH2:13][C:14]=2[CH:20]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCl)cc(Cl)c1O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reaction time: 3 h

Procedure:
Aqueous sodium hydroxide (0.78 g, 19.6 mmol in 45 mL water) was added to a solution of Example 102 (3.21 g, 6.53 mmol) in tetrahydrofuran (45 mL). It was stirred for 3 h, partially concentrated, treated with dil. HCl to pH 7, filtered, washed with water and dried to obtain the title compound as a white solid. Yield: 3.01 g (97%). 1H NMR (CDCl3+DMSO-d6): δ 2.40 (s, 3H, CH3), 3.4 (t, 4H, 2CH2), 3.5 (t, 4H, 2CH2), 4.5 (s, 2H, CH2), 6.4 (d, 1H, Ar), 6.5 (d, 1H, Ar), 7.7 (d, 1H, Ar), 8.1 (d, 1H, Ar); MS: m/e (CI+) 478 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26]CC)[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[Si](I)(C)(C)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C1COCC1>[OH:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Agent: C[Si](C)(C)I
Solvent: C1CCOC1
Product: CS(=O)(=O)C[C@H](c1ccc(O)c(O)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 4.7 %

Procedure:
A mixture of (S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)isoindolin-1-one (5 g, 12.4 mmol) and neat TMSI (25 g, 125 mmol) was heated at 80° C. for 16 hours. The mixture was cooled to room temperature and quenched with 5% aq. sodium sulfite. Ethyl acetate was added and the layers were separated. The organic layer was washed with water, brine and then dried over Na2SO4. The organic layer was concentrated, followed by a solvent swap to THF. To the THF solution, was added cyclopropanecarbonyl chloride (1.2 mL, 13.2 mmol). The mixture was heated to 40° C. for 0.5 hour then cooled to room temperature. The mixture was quenched with 1 N aq. NaHCO3 then extracted with ethyl acetate. The organic was washed with 1 N aq. NaHCO3, water, then brine. The solvent was removed and the crude was suspended in ACN at 40° C. for 1 hour. The product was collected by filtration to give 1 g of crude, 19% yield. Further purification by prep-HPLC followed by treatment with 2 N aq. HCl gave (S)—N-(2-(1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (0.25 g, 5% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 minutes Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 10.91 minutes. 1H-NMR (DMSO-d6): 10.51 (1H, s), 9.02-9.07 (2H, d), 8.22-8.25 (1H, d), 7.48-7.53 (1H, t), 7.18-7.20 (1H, d), 6.70-6.78 (3H, m), 5.77-5.81 (1H, m), 4.59-4.65 (1H, d), 3.86-4.26 (3H, m), 3.02 (3H, s), 1.76-1.83 (1H, m), 0.88-0.90 (4H, m). LC-MS ES+ (M+1) 431.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>C(Cl)Cl>[F:15][C:16]([F:30])([F:31])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)[C:20]([N:13]1[CH2:12][CH2:11][NH:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14]1)=[O:21]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc(C2CNCCN2)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To a cooled solution of CH2Cl2 (103 mL) containing 2-(3,4-dichlorophenyl)piperazine (1.15 g 5.0 mmol), 3,5-bis-(trifluoromethyl)benzoic acid (1.34 g, 5.09 mmol), and N-hydroxybenzotriazole monohydrate (0.688 g, 5.09 mmol) at -20° C. were added Et3N (0.711 mL 5.09 mmol) and N,N-dimethylaminopropyl-ethylcarbodimide (DEC) (0.967 g, 5.09 mmol) under nitrogen. The reaction was kept at -20° C. for an hour and gradually warmed to RT overnight. After stirring 20 h, the reaction was complete and CH2Cl2 (200 mL) was added. The organic solution was washed with 5% NaHCO3 (80 mL) and brine (80 mL, 2×), dried over MgSO4, filtered and concentrated under vacuum to give 2.1 g of crude product. The product was purified by flash chromatography on flash grade silica gel (120 g), eluting with 2% NH3 -MeOH/CH2Cl2 to give a foam solid (1.25 g, 2.65 mmol, 53%). m.p. 50°-53° C.; FAB MS [M+1]+ 470.9;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:34][C@@H:35]1[C:47](=[O:48])[N:37]2[C@@H:38]([C:44]([OH:46])=[O:45])[C@@:39]([Cl:43])([CH3:42])[CH2:40][S:41][C@H:36]12>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:34][C@@H:35]1[C:47](=[O:48])[N:37]2[C@@H:38]([C:44]([OH:46])=[O:45])[C@@:39]([Cl:43])([CH3:42])[CH2:40][S:41][C@H:36]12)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)O)c1ccccc1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a cooled solution of α-tert.-butoxycarbonylaminophenylacetic acid (1.0 g) and triethylamine (405 mg) in tetrahydrofuran (16 ml), is added isobutylchloroformate (550 mg) at -10°C and the mixture is stirred for 10 minutes. To the solution is added a solution of 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylic acid (870 mg), and triethylamine (405 mg) in a mixture of tetrahydrofuran and water (1:1; 15 ml), and the mixture is stirred for 1 hour at 5°C, and for 1 hour at room temperature. The reaction mixture is evaporated in vacuo to remove tetrahydrofuran, and the resultant solution is diluted with a mixture of water and ethyl acetate (3:1). The aqueous layer is separated, acidified to pH 3 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give 7β-(α-tert.-butoxycarbonylaminophenylacetamido)-3β-chloro-3α-methylcepham-4α-carboxylic acid (1.5 g). Yield: 77%.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[C:22]3[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]=1[F:26].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C1COCC1>[F:26][C:9]1[CH:10]=[C:11]([O:12][C:13]2[C:22]3[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)[CH:24]=[CH:25][C:8]=1[NH:7][C:28](=[O:29])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Dry pyridine (125 μL, 1.55 mmol) was added to a suspension of 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (307 mg, 1.13 mmol) in dry THF (20 mL) under Ar and the mixture was cooled to 0° C. Phenyl chloroformate (170 μL, 1.35 mmol) was added dropwise over 5 min and the light brown mixture was stirred at 0° C. for an additional 5 min whereafter the mixture was allowed to warm up to RT and was stirred for 150 min. The brownish mixture was concentrated to dryness and the resulting residue was diluted with EtOAc (60 mL) and H2O (30 mL). The organic layer was isolated and filtered (80 mg of impure product) and the filtrate was washed with aqueous saturated NaHCO3 and brine. The organic layer was evaporated to dryness, re-dissolved in CH2Cl2 and chromatographed on a Biotage 25+M column, eluting with 20%100% EtOAc in CH2Cl2 to give the title compound as a white solid. Yield: 280 mg (81%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH:19][C:15]3[CH:14]=[C:13]4[C:18]([C:10]([C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=5)=[CH:11][NH:12]4)=[CH:17][CH:16]=3)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: Nc1ccc2c(-c3ccc([N+](=O)[O-])cc3)c[nH]c2c1
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ccc2cc(C(=O)Nc3ccc4c(-c5ccc([N+](=O)[O-])cc5)c[nH]c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of 3-(4-nitrophenyl)-1H-indol-6-amine (66.3 mg, 0.26 mmol), 1-methyl-1H-indole-5-carboxylic acid (50.4 mg, 0.29 mmol), hydroxybenzotriazole (3.5 mg, 0.03 mmol) and triethylamine (40.1 μL, 0.29 mmol) in DMF (1.00 mL) was stirred for 5 min before 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (55.2 mg, 0.29 mmol) was added. The reaction was stirred overnight at room temperature and was then diluted with water (5.0 mL). The precipitate that formed was filtered off and sequentially washed with excess methylene chloride and methanol. The solid was recrystallized using hot methanol and gave a bright yellow solid for 1-methyl-N-(3-(4-nitrophenyl)-1H-indol-6-yl)-1H-indole-5-carboxamide (59.8 mg, 0.15 mmol, 56%) after filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Li])[CH:15]=2)[N:10]=1.COC1C=CC2C(=CC=C(C3C=CN=NC=3)C=2)N=1>>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:6]3[N:1]=[N:2][CH:3]=[CH:4][CH:5]=3)[CH:15]=2)[N:10]=1
Reactant: [Li]c1ccc2nc(OC)ccc2c1
Reactant: c1ccnnc1
Agent: COc1ccc2cc(-c3ccnnc3)ccc2n1
Product: COc1ccc2cc(-c3cccnn3)ccc2n1

Procedure:
The following compounds were prepared similarly to the previous Preparation using pyridazine and 2-methoxy-6-lithioquinoline as starting materials. In this case a mixture of 2-methoxy-6-(4-pyridazinyl)quinoline and 2-methoxy-6-(3-pyridazinyl)quinoline was formed which was separated by chromatography on silica (Merck "MK. 60.9385") eluting with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[CH3:18][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:16])[OH:17]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (0.55 g, 2.2 mmol) in anhydrous THF under nitrogen was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 1 mL, 3 mmol) at 0° C. The mixture was slowly warmed to room temperature and kept stirring under nitrogen for 18 hours. The mixture was treated with 10 mL of saturated ammonium chloride aqueous solution and ethyl acetate (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO4). After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford the title compound as an off-white solid: 186-188° C. (HCl salt). Anal. Calc. For C15H17Cl2NO: C, 60.42, H, 5.75, N, 4.7. Found: C, 60.51, H, 5.62, N, 4.56.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.FC1C=CC(C2N=[C:41](C3CCNCC3)[N:42]([CH2:44]CN(C)C)[CH:43]=2)=CC=1C(F)(F)F>>[Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:41][N:42]([CH3:44])[CH3:43])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:29])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=556, obsd.=556).