Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[Cl:35][C:36]1[N:37]=[C:38]([CH3:44])[NH:39][C:40]=1[C:41](O)=[O:42]>CN(C=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:41]([C:40]2[NH:39][C:38]([CH3:44])=[N:37][C:36]=2[Cl:35])=[O:42])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
EDC (0.060 g, 0.311 mmol) and HOBT (0.042 g, 0.311 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.111 g, 0.311 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.050 g, 0.311 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc and saturated sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated. Rerverse phase HPLC (acetonitrile:water with 0.1% formic acid) gave the title compound (0.019 g, 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.86 (br. s., 1H), 8.17 (br. s., 1H), 7.77-7.88 (m, 1H), 7.57-7.66 (m, 1H), 7.46-7.55 (m, 1H), 7.44 (br. s., 1H), 7.22-7.35 (m, 1H), 4.37-4.70 (m, 2H), 2.28 (s, 3H). LCMS: m/z 497, 499.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.Cl.[NH2:24][CH:25]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)C(C)C)(C)C.[O:47]=[C:48]1[N:52]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([NH:59][C:60]([NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])[CH:54]=2)[CH2:51][CH:50]([C:70](O)=[O:71])[CH2:49]1>CN(C)C=O>[F:37][C:33]1[CH:32]=[C:31]([CH:25]([NH:24][C:70]([CH:50]2[CH2:49][C:48](=[O:47])[N:52]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([NH:59][C:60]([NH:62][CH2:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[O:61])[CH:54]=3)[CH2:51]2)=[O:71])[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)CC(N)c1cccc(F)c1
Reactant: O=C(NCc1ccccc1)Nc1cccc(N2CC(C(=O)O)CC2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccc(F)c1
Temperature: 23 °C
Reaction time: 92 h

Procedure:
1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (99.5 mg, 0.52 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole (12.2 mg, 0.090 mmol, 0.2 equiv), methyl 3-amino-3-(3-fluorophenyl)propanoate hydrochloride (118.8 mg, 0.51 mmol, 1.2 equiv), and N,N-diisopropylethylamine (0.18 mL, 1.03 mmol, 2.4 equiv) were added sequentially to a solution of 5-oxo-1-(3-{(benzylamino)carbonylamino}phenyl)pyrrolidine-3-carboxylic acid (152.2 mg, 0.43 mmol, 1 equiv) in N,N-dimethylformamide (3.0 mL). The resulting solution was stirred at 23° C. for 92 hr. The reaction was partitioned between an aqueous solution of hydrochloric acid (1.5 N, 20 mL) and ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, were filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (90% ethyl acetate in hexanes) to give two diastereomers of the title compound (first diastereomer and second diastereomer) as white solids.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.Cl[Sn]Cl.O>CCO>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]nc(Br)c2c1

Procedure:
The product of Step (a) (10.0 g, 41.3 mmol, 1.00 equiv) was suspended in EtOH (120 mL). SnCl2.H2O (46.6 g, 206 mmol, 5.00 equiv) was added and the mixture was refluxed for 18 hours. The reaction mixture was concentrated en vacuo and water was added to the residue. The mixture was basified to pH 8 with satd. NaHCO3 and extracted with EtOAc (3×). The combined organic extracts were washed with satd. NaCl, dried over MgSO4, filtered and concentrated en vacuo. 8.10 g (92%) of the title compound was iolated as a purple solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:8][CH:7]=1
Reactant: Fc1ccccc1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C=C(C)C(=O)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
A slurry of 29.4 g. (0.220 mole) of anhydrous aluminum chloride in 38.4 g. (0.40 mole) of fluorobenzene under nitrogen is cooled to 15°C. Methacrylyl chloride (21.9 g., 0.200 mole) is then added dropwise over 30 minutes while holding the temperature at 15° to 20°C. The mixture is warmed to 30°C over 10 minutes, stirred at 30°C for 10 minutes and quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 4'-fluoro-2-methylacrylophenone.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.ClC1[N:16]=[C:17]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=[C:1]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(CNc2nc(Cl)nc3ncccc23)c(Cl)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(CNc2nc(N3CCNCC3)nc3ncccc23)c(Cl)c1
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Boc-piperazine (122 mg, 0.65 mmol) was added to the solution of (2-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-(2,4-dichloro-benzyl)-amine(185 mg, 0.54 mmol) and N,N-diisopropylethylamine (145 μL, 0.82 mmol) in n-butanol (2 mL). The reaction mixture was stirred at 85° for 10 h. All starting material was consumed as seen on HPLC. The reaction mixture was concentrated at room temperature under vacuo. The resulting residue was suspended in 2 mL of TFA-CH2Cl2 (1:1) mixture and stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with CH2Cl2 (2×10 mL), dried (Na2SO4) and concentratd to furnish (2,4-Dichloro-benzyl)-(2-piperazin-1-yl-pyrido[2,3-d]pyrimidin-4-yl)-amine(210 mg) as pale brown oil. The crude was carried forward as such in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=1.[H-].[Na+]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Yield: 76.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-hydroxythiophenol (1.26 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (2.86 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:10]=[C:9]([NH:11][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:18])[CH3:13]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(N)c1
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OCC)c1

Procedure:
By the procedure similar to that described in Example 1, 2,4-diaminobenzoic acid was condensed with 2-ethoxybenzoylchloride to obtain 2,4-bis(2'-ethoxybenzamido)-benzoic acid having a melting point between 225° - 226°C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]([C@H:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)[CH3:13].[CH2:20](I)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C@@H:15]1[C@@H:14]([CH:12]([CH3:13])[CH3:11])[CH2:19][O:18][C:16]1=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 92 mL, 92 mmol) was added in 3 to 5 minutes to a solution of (S)-β-(2-propyl)-γ-butyrolactone 175 (11.68 g, 91.25 mmol) in dry THF 100 mL at −78° C. under argon atmosphere. It was stirred for 1 hour and a solution of benzyl iodide (21.87 g, 100.37 mmol) in dry THF was added rapidly. Stirring was continued for 1.5 hours and quenched at −78° C. by the addition of a solution of brine followed by ethyl acetate. The organic phase was separated and the aqueous was further extracted with ether. Chromatography on silica gel first eluted with 5% methylene chloride in pet ether, and finally with 10% ether in pet ether gave desired compound 11.6 g, 58%. NMR (CDCl3) δ 7.19 (m, 5H, C6H5), 4.02 (app. t, 1H, CHaHbO), 3.87 (dd, 1H, CHaHbO), 2.98 (d, 2H, ArCH2), 2.57 (q, 1H, BnCHC═O), 2.05 (m, 1H, CHCH(Me)2, 1.55 (m, 1H, CH(Me)2), 0.81 (d, 3H, CH3) and 0.72 (d, 3H, CH3).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH2:19])[CH2:11][CH2:10]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl>[CH3:20][N:21]([CH3:25])[C:22]([NH:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[CH2:10][CH2:11]1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: NC1CCC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NC1CCC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
In 25 ml of dichloromethane containing 2.8 ml of triethyl amine, 2,32 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine are added followed by 2.16 g of dimethylcarbamoyl chloride. The mixture is heated at reflux for 3 hours, cooled to room temperature, washed successively with 50 ml of H2O, 50 ml of 3N NaOH, 50 ml of 3N HCl and 50 ml of H2O. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is recrystallized from toluene to give the title compound, melting point 157° C to 162° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]4)[C:16]([C:33]([F:36])([F:35])[F:34])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]4)[C:16]([C:33]([F:35])([F:34])[F:36])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CCNCC4)c3)ncc2C(F)(F)F)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A mixture of 1-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 66 (0.081 g, 0.16 mmol) and formaldehyde (37 wt % in H2O; 36 μL, 0.49 mmol) in MeOH (5 mL) was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (0.137 g, 0.649 mmol) was then added and stirring was continued for 3 hours at room temperature. The volatiles were removed in vacuo and sat. aq. NaHCO3 (20 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×20 mL) and the combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The yellow residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 2% v/v aqueous ammonia in MeOH to release the amine product. The solvent was evaporated under reduced pressure, the residue was taken up in DCM and a solid was precipitated by the addition of petroleum benzine 40-60° C. The solid was isolated by filtration and air dried to give the title compound 67 as a yellow solid (0.048 g, 58%). LCMS-A: rt 4.82 min; m/z 514 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 5.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine and 6.86 g. of ethyl carbazate in 80 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled in an ice bath and the resulting solid filtered, washed with n-butyl alcohol, water and dried. The product is recrystallized from ethanol to give crystalline material, m.p. 190°-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH3:22])[CH:16]=[C:15]([CH3:23])[N:14]=1>>[CH3:22][C:17]1[CH:16]=[C:15]([CH3:23])[N:14]=[C:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:6][CH:7]=2)[C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(O)Cc1ccc(N)cc1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CC(C)O)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 1-(4-aminophenyl)-2-propanol (step 1) and 2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of Example 1).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH3:31][S:32][CH2:33][C:34](Cl)=[O:35].[OH-].[Na+]>CC(C)=O>[CH3:31][S:32][CH2:33][C:34]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:17][N:18]=[N:19][N:20]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:35]
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CSCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CSCC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 10.2 g. (0.026 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml. of 3% sodium bicarbonate and 220 ml. of acetone is dropwise added a solution of 3.66 g. (0.029 mol.) of methylmercaptoacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3 N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: N[C@@H](Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32; 2,6-dichloro-quinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-bromo-pyridin-2-yloxy)-phenyl]-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[C:18]=2[O:31]CC2C=CC=CC=2)[CH:7]=[C:6]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:5]=1.[H][H]>[Pd]>[CH3:1][O:2][C:3](=[O:50])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=2[OH:31])[CH:7]=[C:6]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:5]=1
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)OC)c1
Reaction time: 4.5 h
Yield: 87.4 %

Procedure:
A mixture of 0.7 g of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy) phenyl]hexyl]oxy]benzoic acid methyl ester and 0.3 g of 10% palladium on carbon was stirred in a hydrogen atmosphere until uptake ceased after 4.5 hours. After the usual workup, the crude product was triturated with hexane and filtered to give 0.45 g (87% yield, mp 71°-72°) of 3-(decyloxy)-5-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:17]=[CH:18][N:19]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=2.[Br:20]N1C(=O)CCC1=O>ClCCl>[Br:20][C:17]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:19][CH:18]=1)=[CH:9][C:8]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:7][CH:6]=3
Reactant: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1ncc(Br)n12
Temperature: 30 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 4-chloro-7-(trifluoromethoxy)imidazo[1,2-a]quinoxaline (5.4 g, 18.8 mmol, 1 eq) prepared as described in example 7 step 4 in dichloromethane (94 mL) is added N-bromosuccinimide (5.0 g; 28.2 mmol; 1.5 eq). The solution becomes green during the addition. The solution is allowed to stir for 7 hours at 30° C. until completion of the reaction. Then, the solution is concentrated under vacuum and purified by chromatography on a silica gel column (chloroform/cyclohexane 7:3) to afford the title compound still contaminated by 10% of residual N-bromosuccinimide (7.2 g; 17.7 mmol; 94%). The compound is used as such in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:42]5[CH:41]=[C:40]([F:39])[CH:45]=[CH:44][C:43]=5[OH:49])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1cc(F)ccc1O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 75.1 %

Procedure:
To (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.24 g, 0.41 mmol, 1 equiv), (5-fluoro-2-hydroxyphenyl)boronic acid (96 mg, 0.62 mmol, 1.5 equiv), and Pd(PPh3)4 (47 mg, 0.041 mmol, 0.1 equiv) was added DMF (4.1 mL that had been degassed by sparging with nitrogen for 10 min) Na2CO3 (0.41 mL of a 2 M aqueous solution, 0.82 mmol, 2 equiv) was added and the reaction was heated to 90° C. for 3 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-60% acetone in hexane) to provide the product as a yellow foam (0.19 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.13-8.08 (m, 1H), 8.05-8.00 (m, 1H), 7.67-7.48 (m, 3H), 7.09-6.94 (m, 4H), 6.07-5.92 (m, 1H), 5.45-5.36 (m, 1H), 5.22-5.07 (m, 2H), 4.04-3.97 (m, 2H), 3.81-3.77 (m, 3H), 3.77-3.74 (m, 4H), 2.74-2.65 (m, 3H), 2.08-1.94 (m, 3H), 1.80-1.68 (m, 1H), 1.36 (s, 3H), 1.24 (s, 9H). LCMS (M+1)=617.35.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:26]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1>[Pd].C(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:26])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Temperature: 50 °C
Reaction time: 13 h
Yield: 103.8 %

Procedure:
A suspension of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-cyclohexyl-amine (10 g, 25.0 mmol) and palladium on carbon (2.7 g, 10%, wet, Degussa, E101 NE/W) in a 3:1 mixture of THF and ethanol (200 ml) was stirred under a hydrogen atmosphere (2-3 balloons) at 50° C. for 13 h. The reaction mixture was cooled to 25° C. then was filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude 1-benzenesulfonyl-N-4-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (9.61 g, 100%) as a rose foam. LCMS (Method G, ESI): RT=0.83 min, m+H=371.2. This material was used in subsequent reactions without additional purification or characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1[CH2:17][CH2:16][NH:15]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:17][CH2:16][NH:15][C:11]2=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: O=C1NCCO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCCN1c1cccc([N+](=O)[O-])c1
Temperature: 195 °C
Yield: 33 %

Procedure:
A mixture of 3-nitrophenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 33 percent of the desired product, m.p. 158° C-160° C.