Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=CC=1)([O-])=O>CC#N>[CH:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1)([CH3:41])[CH3:40]
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CC#N
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C(C)C)cc4)CC3)c2cc1OC
Yield: 71.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (18.8 mg, 68.9 μmol), as prepared in Example 1d, and (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester 21.3 mg, 71.0 μmol), as prepared in the preceding step, was stirred in CH3CN (250 μL) at 80° C. for 4 h. The reaction was then partitioned with DCM (4 mL) and 1 M K2CO3 (4 mL), and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (EtOAc) provided the title compound (21.5 mg, 72%). 1H-NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.25 (m, 3H), 7.16 (m, 2H), 6.37 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (tt, 1H), 3.18 (td, 2H), 2.87 (heptet, 1H), 2.24-2.08 (m, 2H), 2.04-1.94 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 434.2, found 435.3 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:14][N+:15]([CH3:17])=C.[I-].[C-]#N.[K+]>C(#N)C.C(OCC)(=O)C>[C:9]([CH2:8][C:7]1[C:6]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=[CH:2][C:17]=2[NH:15][CH:14]=1)#[N:1]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: C=[N+](C)C
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc2[nH]cc(CC#N)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl indole-4-carboxylate (1.1 g 6.2 mmol) and Eschenmoser's salt [N,N-dimethylmethyleneammonium iodide] (1.3 g, 7 mmol) in acetonitrile (15 ml) is refluxed for 3 hours. The reaction mixture is concentrated, redisolved in dichloromethane (400 ml) and washed with 1M sodium hydroxide (200 ml) and water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The resulting methyl 3-(dimethylaminomethyl)indole-4-carboxylate (1.2 g) is methylated with methyl iodide (0.7 ml) in a mixture of dichoromethane (25 ml) and ether (13 ml). The reaction mixture is concentrated, the product dissolved in DMSO (7 ml) and treated with potassium cyanide (700 mg, 10 mmol). After stirring at r.t. overnight the reaction mixture is diluted with ethyl acetate (200 ml) and washed with three portions of water (100 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 2:3 to give methyl 3-(cyanomethyl)indole-4-carboxylate as a dark oil. Hydrogenation in acetic acid over platinum oxide gives the desired intermediate as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:24])=[N:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 82.3 %

Procedure:
A mixture of 7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (2.01 g, 7.04 mmol), phosphorus oxychloride (5.16 mL, 56.35 mmol) and N,N-dimethylaniline (0.89 mL, 7.04 mmol) in 1,2-dichloroethane was heated to 80° C. for two h. The mixture was allowed to cool to r.t. and poured over crushed ice (100 mL). The mixture was made basic (pH=˜8) by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated to leave a dark oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to yield 1.76 g (82%) of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]([OH:26])[C:32]([F:35])([F:34])[F:33])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C(F)(F)F)C1=O
Reaction time: 1 h

Procedure:
A solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (80 mg, 0.186 mmol) and trimethyl(trifluoromethyl)silane (82 μL, 0.558 mmol) in THF (929 μL) was treated at 0° C. with 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol). After being stirred for 1 h, three additional equivalents of trimethyl(trifluoromethyl)silane (82 μL, 0.558 mmol) and 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol) were added to the reaction at 0° C. and the reaction was stirred for 14 h. The reaction mixture was diluted (EtOAc), washed (1×H2O and 1×sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by reverse phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 90% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided two compounds which are diastereomers at the secondary alcohol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: NCCN1CCCC1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 1-chloro-4-(isopropylsulfonyl)-2-nitrobenzene (Step C of Example 1, 200 mg, 0.76 mmol) and 1-(2-aminoethyl)pyrrolidine (0.1 mL, 0.80 mmol) in ethanol (1 mL) was microwaved for 15 min at 130° C. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was crude product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].CO[C:18](OC)([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>CC(C)=O>[CH3:19][C:18]1([CH3:20])[O:15][C:2]([CH3:1])([CH3:14])[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[O:4]1
Reactant: COC(C)(C)OC
Reactant: CC(C)(O)C(O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)C(C)(C)O1
Yield: 84.1 %

Procedure:
A solution of 2-methyl-1-(4-nitrophenyl)propane-1,2-diol (1.5 g, 7.1 mmol), 2,2-dimethoxypropane (1.45 g, 14.2 mmol) and TsOH (cat., 260 mg, 1.5 mmol) in acetone (40 mL) was stirred at 30° C. for 16 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography, eluting with PE:EA (8:1), to obtain the desired product (1.5 g, 85% yield) as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 8.23 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=9.0 Hz), 4.93 (s, 1H), 1.59 (s, 3H), 1.48 (s, 3H), 1.46 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(Oc2ccc(-c3nc(-c4ccccc4)c(-c4ccccc4)o3)cc2)cc1
Yield: 97.9 %

Procedure:
A mixture containing one gram (3.2 mmoles) of 4,5-diphenyl-2-(p-fluorophenyl)-1,3-oxazole, 1.2 g (12 mmoles) of phenol, 2 g (14.5 mmoles) of anhydrous potassium carbonate and 10 ml of N-methylpyrrolidone (hereinafter NMP) is stirred and refluxed under nitrogen atmosphere for 40 minutes when gas chromatograph analysis indicates the disappearance of the starting material and the formation of a new compound. The reaction mixture is cooled, diluted with 30 ml of water, and stirred for 30 minutes. The colorless precipitate is filtered and recrystallized from 95 percent ethanol. The title compound (1.22 g, 99 percent yield) is recovered. The product has a melting point of 125° C.-126° C.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](O)[CH3:13].[ClH:15]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([Cl:15])[CH3:13]
Reactant: Cl
Reactant: CC(O)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(Cl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Thionyl chloride (1.49 g, 12.6 mmol) was added to 1-(2-chlorophenyl)ethanol (1.0 g, 6.3 mmol) in toluene (50 mL) and the mixture was allowed to stir at room temperature for 2 h. To the reaction mixture was added 10% aq. HCl solution (20 mL). The organic phase was separated and washed with another portion of 10% aq. HCl solution, brine (20 mL) and then separated, dried and evaporated to provide 1-chloro-2-(1-chloroethyl)benzene in 72% yield.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1(C#N)[CH:11]=[CH:10][CH:9]=[CH:8][NH:7]1.C[Mg]Br.[Cl-].[NH4+].[O:19]1CC[CH2:21][CH2:20]1>C(OCC)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[N:7]=[C:8]([C:20](=[O:19])[CH3:21])[CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(C2OCCO2)C=CC=CN1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1cccc(C2OCCO2)n1
Temperature: -10 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.88 g of 2-[1,3]dioxolan-2-yl-pyridine-2-carbonitrile (4.99 mmol) is dissolved in 10 ml of tetrahydrofuran. 3.50 ml of a 3M solution of methylmagnesium bromide in diethyl ether are introduced dropwise into the solution cooled to -10° C. The reaction mixture is stirred for 3 hours at room temperature under a nitrogen atmosphere. The mixture is poured into a saturated aqueous solution of ammonium chloride, the mixture is extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of ammonium chloride and then dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform). 0.80 g of a yellow oil is recovered.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH2:25]([O:32][C:33]1[CH:60]=[CH:59][C:58]([CH2:61]CO)=[CH:57][C:34]=1[C:35]([NH:37][C:38]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=[CH:47][C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:60]=[CH:59][C:58]([CH2:61][CH2:20][Br:24])=[CH:57][C:34]=1[C:35]([NH:37][C:38]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=[CH:47][C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 84 %

Procedure:
Triphenylphosphine (0.13 g) and carbon tetrabromide (0.16 g) were added to a methylene chloride (3.4 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-hydroxyethyl)benzamido)-4-phenylbenzoate (0.17 g), followed by stirring at room temperature for 50 minutes. The reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] and then purified by silica gel column chromatography [eluent: 100-85% hexane/ethyl acetate] to obtain 0.16 g of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethyl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH3:13].C([Mg]Cl)(C)C.[Li+].[Cl-].[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH3:13])[CH2:31][CH2:32][CH3:33]
Reactant: Cc1nc(-c2cccnc2)sc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccnc2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In a dry flask under argon, 5-bromo-4-methyl-2-(3-pyridyl)thiazole (15.00 g, 55.85 mmol) was dissolved in THF (140 mL), and with cooling to keep the temperature at 25°-30° C., treated dropwise with i-PrMgCl.LiCl (TurboGrignard, 60 mL, 78.19 mmol,). The resulting mixture was allowed to stir at ambient temperature for 1 hour. The reaction mixture was then cooled to 10° C., and tri-n-butyl tin chloride (19 mL, 67.02 mmol) was added over 5 min. The reaction was stirred for 30 min at ambient temperature and then at reflux (66° C.) for 18 hours. The reaction mixture was quenched with saturated NH4Cl solution and diluted with ethyl acetate. Then aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers washed with brine, dried over MgSO4, filtrated and evaporated. Purification by Combi flash chromatography with a column of 24 g and a gradient cyclohexane: 0-100% ethyl acetate to give the title compound as a yellow solid (9.17 g, 26%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[CH:16][CH:15]=[CH:14][C:13]=2[NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[CH:16][CH:15]=[CH:14][C:13]=2[NH:24][C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 3-tert-butoxycarbonylamino-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (869 mg) in dichloromethane (2 ml) was added trifluoroacetic acid (5 ml) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from isopropyl alcohol to give 3-amino-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (581.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 85.7 %

Procedure:
In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser were placed fluorobenzene (117 g, 1.2 mol) and 4-bromobenzoyl chloride (39.8 g, 0.181 mol). The mixture was cooled to 0° C. and aluminum chloride (27 g, 0.20 mol) was added. The mixture was stirred for 15 minutes at 23° C., followed by heating to reflux for 4 h. The reaction was then cooled to 23° C. and stirred for 16 h. The resulting slurry was poured into 2 L of acidic (HCl) water. The organics were extracted with methylene chloride, and dried over magnesium sulfate. The slurry was filtered and the methylene chloride was removed under reduced pressure to yield an off white powder. Recrystallization from ethanol afforded 43.3 g (86%) of 4-bromo-4'-fluorobenzophenone as white crystals: m.p. 106°-107° C., (Lit. 107°-108° C.).
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].C=O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:3]2[C:2]=1[NH:1][CH2:17][N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: C=O
Solvent: CCO
Product: Cc1cccc2c1NCN(C(C)C)C2=O
Yield: 95 %

Procedure:
To a solution of 2-amino-3-methyl-N-(1-methylethyl)benzamide (0.5 g, 2.6 mmol) in ethanol (10 mL) was added paraformaldehyde (78 mg, 2.6 mmol) and p-toluenesulfonic acid (18 mg, 95 μmol) and the mixture was heated at reflux until it became clear (approximately 4 hours). The solvent was removed under reduced pressure to give the title compound (95% pure) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: O=C(O)c1ccccc1F
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15]Br>C(O)(=O)C.CN(C)C=O>[Br:15][C:12]1[S:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=Cc1cc(-c2cccnc2F)cs1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
4-(2-Fluoropyridin-3-yl)thiophene-2-carbaldehyde (3.35 g) was dissolved in acetic acid (20 mL) and N,N-dimethylformamide (20 mL), and bromine (7.77 g) was added at room temperature. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residue was weakly basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=6:1→3:1), and the obtained solid was washed with diisopropyl ether to give the title compound as a pale-yellow powder (yield 1.79 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:13][C:10]1[CH:9]=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH2:11][CH3:12])=[N:5][C:6]=12
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc(Cl)n2ncc(Cl)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.5 g (30 mmol) of the chloro compound (Example 1, Step B) and 4.0 g (30 mmol) of N-chlorosuccinimide were dissolved in 150 ml chloroform, stirred for 4 h at room temperature, and finally heated for some minutes on a steam bath. The mixture was poured on to ice water, the aqueous layer extracted with dichloromethane, the combined organic layers washed twice with saturated sodium carbonate solution, dried over sodium sulfate, and evaporated in in vacuo. The title compound was obtained as an oil after chromatography on silica gel with dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH2:42])=[C:35]2[CH2:34][CH2:33]1>>[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH:42][C:24]3[C:23]([C:21]([NH:20][C:12]4[CH:11]=[C:10]5[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]5)=[CH:14][CH:13]=4)=[O:22])=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:35]2[CH2:34][CH2:33]1
Reactant: NCc1ccnc2c1CCN2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc2C(C)(C)C1

Procedure:
The titled compound was prepared from 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 529 (M+H). Calc'd. for C30H36N6O3—528.65.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:29]3[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1ccc(I)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(Br)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester and 1-bromo-4-iodo-benzene.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: OB(O)c1ccc(O)cc1
Product: CC(C)N1CCN(c2ccc(-c3ccc(O)cc3)nn2)CC1

Procedure:
4-[6-(4-Isopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenol was prepared by the general procedure I similar to that described in Example 71, starting from 3-chloro-6-(4-isopropyl-piperazin-1-yl)-pyridazine and (4-hydroxyphenyl)boronic acid.