Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:22](=[O:23])[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(N)n(-c2ccc(Cl)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)Oc2ccccc2)n(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26.1 %

Procedure:
1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-amine (100 mg, 0.48 mmol) was dissolved in dry THF (6 mL). Pyridine (51 μL, 0.62 mmol) was added and the solution was cooled in an ice bath under nitrogen surpressure. Phenyl chloroformate (73 μL, 0.58 mmol) was slowly added and the mixture was stirred at 0° C. during 5 min and at room temperature during 1.5 h. The mixture was then diluted in EtOAc (10 mL) and the salts remaining were filtrated off. The filtrate was concentrated under reduced pressure. The resulting white solid was washed with a little amount of cold EtOAc and water to afford the title compound (41 mg, 26%) as a white solid. 1H-NMR (δ, ppm, DMSO-d6): 2.22 (s, 3H, CH3), 6.28 (s, 1H, HPyz,4), 7.11-7.60 (m, 9H, Harom), 10.14 (bs, 1H, NH). LC-MS (m/z): 328 (M+H, 100).
Reaction SMILES: [C:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([C:21]([F:24])([F:23])[F:22])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(OCC)(=O)C>C1COCC1>[C:1]1([C:7]2[C:16]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]([F:24])([F:22])[F:23])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc2c(c1)C1OCCCC1C(c1ccccc1)N2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCc1cc2cc(C(F)(F)F)ccc2nc1-c1ccccc1
Reaction time: 8 h

Procedure:
0.50 g (1.50 mmol) of 5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 3 was dissolved in THF (15 ml), 1.65 g (3.00 mmol, 2 eq) of cerium(IV) ammonium nitrate were added at RT, and stirring was continued overnight at RT. When the reaction was complete, 50 ml of ethyl acetate were added, and the mixture was extracted 2× with 50 ml of water. The org. phase was dried and evaporated to dryness. The residue was recrystallised from ethyl acetate/diethyl ether, giving a pale-yellow solid (compound 4).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:7](=[O:20])[CH2:6][C:5]1=[O:21])[CH3:3].CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:46]=[N+:47]=[N-:48])(=O)=O)(C)C.C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[N:46]([CH:6]1[C:5](=[O:21])[N:4]([CH:2]([CH3:1])[CH3:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]1=[O:20])=[N+:47]=[N-:48]
Reactant: CC(C)N1C(=O)CC(=O)N(CC(F)(F)F)c2ccccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1C(=O)C(N=[N+]=[N-])C(=O)N(CC(F)(F)F)c2ccccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a stirring solution of 1-(2-propyl)-5-(2,2,2-trifluoroethyl)-1,5-benzodiazepine-2,4-dione (440 mg, 1.46 mmole) in tetrahydrofuran (12 mL), which was cooled to -78° C. in a dry ice/acetone bath, was added dropwise potassium tert-butoxide (1M in tetrahydrofuran, 1.61 mL, 1.61 mmole). After ten minutes, 2,4,6-triisopropylbenzenesulfonyl azide (495 mg, 1.61 mmole) in tetrahydrofuran (5 mL) was added dropwise. After ten minutes, acetic acid (0.35 mL,5.84 mmole) in tetrahydrofuran (5 mL) was added in one portion and the reaction was warmed to room temperature over three hours. The reaction was poured into a solution of saturated sodium hydrogen carbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:3 ethyl acetate:hexane to give 350 mg of product identified as the axial conformer and 35 mg of the equatorial isomer. NMR data is given for the major isomer.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:37][CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[F:33])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1ccccc1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NCc1ccccc1F)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 52 mg, 0.42 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. Tetrahydrofuran (2 mL) was added to dissolve the solid, and lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight, and then another portion of lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (75 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.10 (t, J=5.8 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.40 (t, J=7.7 Hz, 1H), 7.29-7.36 (m, 1H), 7.16-7.23 (m, 2H), 4.56 (d, J=5.8 Hz, 2H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][N:4]=1)=O.OS(O)(=O)=O.[CH:18]([O:23][CH3:24])([O:21][CH3:22])OC>CO>[CH3:24][O:23][CH:18]([O:21][CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(C(OC)OC)nc1
Yield: 75 %

Procedure:
To a solution of methyl 2-formylpyridine-5-carboxylate (2.00 g, 12.1 mmol) in methanol (20 ml) and trimethyl orthoformate (5 ml) was added H2SO4 (conc., 1.5 ml). After refluxing overnight, the reaction was cooled and concentrated to a thick slurry and then poured into saturated NaHCO3 (50 ml). The latter was extracted with ether (3×30 ml) and the combined organic layers dried (MgSO4) and concentrated to afford title product (1.91 g, 75%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:31][O:32][CH:33]([F:35])[F:34])[C:10]([NH:12][C@@H:13]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])=O)(C)(C)C.[ClH:36]>C(OCC)C>[ClH:36].[NH2:8][C@@H:9]([CH2:31][O:32][CH:33]([F:34])[F:35])[C:10]([NH:12][C@@H:13]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Benzyl(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3 (difluoromethoxy)propanoyl]amino]-3-phenyl-propanoate (1.9 g, 3.86 mmol) was stirred in HCl, 2M in diethyl ether (12 mL), at room temperature overnight. The resulting suspension was diluted with hexanes and the filtered to collect the compound of Formula XVI(a) (1.65 g, quantitative yield) as a white solid. The product was used directly in the subsequent reaction.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:34])[C:19]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:20][O:21][CH:22]3[CH2:26][CH2:25][O:24][C:23]3=[O:27])[C:15](=[O:35])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:40]>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:34])[C:19]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:20][O:21][CH:22]3[CH2:26][CH2:25][O:24][C:23]3=[O:27])[C:15](=[O:35])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:40]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3CCOC3=O)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC3CCOC3=O)c3csc(N)n3)[C@H]2SC1

Procedure:
A solution of 0.283 g of the product of Example 8, 1 ml of 1 M sodium acetate in methanol and 1 ml of methanol was treated with 30 g of activated carbon and the mixture was filtered. The filter was rinsed 3 times with methanol and the filtrate was evaporated under reduced pressure at a temperature less than 30° C. to a volume of 1 ml. The solution was diluted with 10 ml of ethanol at 100° C. and was vacuum filtered. The mixture was rinsed with 100° C. ethanol and then with ether to obtain 0.165 g of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-oxo-3-tetrahydrofuranyloxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]=[O:14])=[C:8]2[C:3]=1[C:4]([CH2:16][CH2:17][CH3:18])=[CH:5][C:6](=[O:15])[O:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([CH3:30])([CH3:29])[C:27]#[CH:28]>CC(=O)CC.CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Cl-].[Zn+2]>[OH:12][C:10]1[C:9]([CH:13]=[O:14])=[C:8]2[C:3]([C:4]([CH2:16][CH2:17][CH3:18])=[CH:5][C:6](=[O:15])[O:7]2)=[C:2]2[O:1][C:26]([CH3:30])([CH3:29])[CH:27]=[CH:28][C:11]=12
Reactant: C#CC(C)(C)Cl
Reactant: CCCc1cc(=O)oc2c(C=O)c(O)cc(O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCCc1cc(=O)oc2c(C=O)c(O)c3c(c12)OC(C)(C)C=C3
Temperature: 60 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
To a solution of 6 (5.60 g, 22.5 mmol) in 2-butanone (125 mL) and dry DMF (10 mL) was added potassium carbonate (13.2 g, 95.5 mmol), tetrabutylammonium iodide (12.2 g, 33.0 mmol) and 3-chloro-3-methyl-1-butyne (11.2 g, 109 mmol). The reaction mixture was heated at 60° C. for 1 h, at which time anhydrous ZnCl2 (16 mL, 1 M solution in ether) was added. The reaction mixture was then heated at 60° C. for 12 h. Additional anhydrous ZnCl2 (8 mL, 1M solution in ether) was added, and the reaction mixture was kept at 60° C. for another 24 hr. The reaction mixture was cooled, quenched with saturated aqueous NH4Cl (150 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were then washed with brine (1×50 mL), dried (MgSO4), concentrated and submitted to silica gel chromatography (solvent B) to obtain 7 (4.46 g, 63%) as a yellow solid: mp 116°-117° C.; 1H NMR (3:2 CDCl3 -CD3OD): δ 1.08 (t, J=7.3 Hz, 3H, --CH2CH3), 1.57 (s, 6H, --C(CH3)2), 1.68 (m, 2H, --CH2CH3), 2.90 (t, 2H, J=7.7 Hz, --CH2CH2CH3), 5.67 (d, 1H, J=10.0 Hz, H-3), 6.02 (s, 1H, H-9), 6.62 (d, 1H, J=10.0 Hz, H-4), 10.29 (s, 1H, --CHO); 13C NMR (3:2 CDCl3 -CD3OD): δ 12.79, 22.44, 27.15, 37.76, 79.87, 102.02, 103.08, 104.74, 110.18, 113.91, 126.31, 157.30, 157.54, 158.09, 158.91, 160.21, 192.12. Anal. Calcd for C18H18O5 : C, 68.78; H, 5.77. Found C, 68.77; H, 5.79.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[N:3]=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([Cl:16])=[O:15])[N:3]=1
Reactant: Cc1nc(-c2ccccc2N)no1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2NC(=O)Cl)no1
Reaction time: 17 h

Procedure:
A solution of 2-(5-methyl-1,2,4-oxadiazol-3-yl)benzeneamine (1.0 g) in dry dichloromethane (20 ml) was added dropwise to a solution of phosgene (14.1 ml) in dichloromethane (50 ml) at 0° under a nitrogen atmosphere. The opaque solution was then allowed to slowly attain room temperature and stirred for 17 h. The reaction mixture was concentrated under vacuo to give a pale yellow solid (1.3 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=O.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(Cc4ccccn4)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.5 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (88 mg, 0.18 mmol) (as prepared in Example 14, step (b)), pyridine-2-carbaldehyde (17 μL, 0.21 mmol), NEt3 (30 μL, 0.21 mmol), sodium triacetoxyborohydride (56 mg, 0.25 mmol) and 0.8 mL of 1,2-dichloroethane and stirred for 10 h at 25° C. The solvent was evaporated, and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 20 min to give 81 mg (78%) of a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.88 (dd, 1H), 7.58 (d, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.76 (m, 1H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.20 (m, 4H), 2.00 (m, 4H), 1.72 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C28H30N6O, 467.2 (M+H). found 467.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH2:24][CH2:23]1>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30][C:31]([O:1][CH2:2][C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]3)=[CH:5][CH:4]=2)=[O:32])[CH2:26][CH2:27]1
Reactant: O=C1CCc2ccc(CO)cc2N1
Reactant: COc1ccccc1N1CCN(CCCC(=O)O)CC1
Product: COc1ccccc1N1CCN(CCCC(=O)OCc2ccc3c(c2)NC(=O)CC3)CC1

Procedure:
(2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl 4-(4-(2-methoxyphenyl)piperazin-1-yl)butanoate (38c) (Scheme 7) was prepared from the carbinol 37 and the carboxylic acid 18c according to the protocol described for the compound 38a (Example 55). Colorless oil, 0.15 g (41%). 1H NMR (400 MHz, CDCl3): δ 1.84 (quintet, J=7.2 Hz, 2H); 2.38-2.54 (m, 4H); 2.58-2.60 (m, 6H); 2.95 (t, J=8.4 Hz, 2H); 3.03 (broad s, 4H); 3.80 (s, 3H); 5.02 (s, 2H); 6.80-6.94 (m, 4H); 7.09 (d, J=7.6 Hz, 1H); 9.30 (m, 1H). MS (ESI): m/z=438.20 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([NH:22][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:35]([C:36](=[O:39])[NH:37][CH3:38])=[CH:34][CH:33]=[CH:32][C:31]=4[F:40])[C:26]([Cl:41])=[CH:25][N:24]=3)=[CH:21][C:15]=2[NH:14][C:13](=[O:42])[CH2:12]1)=O)C1C=CC=CC=1>CSC.FC(F)(F)C(O)=O>[Cl:41][C:26]1[C:27]([NH:29][C:30]2[C:31]([F:40])=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]([NH:37][CH3:38])=[O:39])=[N:28][C:23]([NH:22][C:20]2[CH:19]=[CH:18][C:16]3[CH2:17][NH:11][CH2:12][C:13](=[O:42])[NH:14][C:15]=3[CH:21]=2)=[N:24][CH:25]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C(=O)OCc2ccccc2)C3)ncc1Cl
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CNC3)ncc1Cl
Yield: 67 %

Procedure:
A solution of 8-[5-chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (0.21 g, 0.36 mmol) in methyl sulfide (3.5 mL) and trifluoroacetic acid (11 mL) was stirred at room temperature for 16 hours. Concentration and chromatography on a silica gel with methylene chloride and methanol (20:1) gave 0.11 g of 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (68% yield): 1H NMR (300 MHz, CD3OD) δ 8.18 (s, 1H), 7.45 (m, 4H), 7.27 (s, 2H), 4.24 (s, 2H), 3.65 (s, 2H), 2.84 (d, 3H); MS (m/e): 456.4 (M+1).
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[C:12]1([CH3:21])[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>O1CCOCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[C:15]1[CH:16]=[CH:17][C:12]([CH3:21])=[CH:13][CH:14]=1)#[N:7]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
7.65 mg of Pd2 (dba)3 (8.35 μmol) and 11.60 mg of Ligand 2 (33.33μmol) were combined in 5 ml of solvent (dioxane, toluene, or 2-propanone) and stirred at room temperature for 2 hours to form a catalyst solution that was used in this example and other examples. CsF (2.28 g, 15.0 mmol), 2-chlorobenzonitrile (0.689 g, 5.00 mmol), and p-tolueneboronic acid (0.748 g, 5.50 mmol) were taken up in 14 ml of dry dioxane under nitrogen and a 0.1 mol % aliquot from the catalyst solution (in dioxane) was added. The mixture was then heated to 80° C. for 12 hours. The mixture was then cooled to room temperature, diluted with Et2O, and extracted with a saturated NH4Cl solution (3×20 ml). The Et2O layer was dried over MgSO4, filtered and concentrated to give a viscous oil which was purified by flash chromatography to give 844 mg of 2-cyano-4'-methylbiphenyl in 87% isolated yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]2([CH3:23])[CH3:22])[CH:15]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:22][C:5]1([CH3:23])[C:4]2[C:13]3=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=3)[CH:15]=[C:2]([B:29]([OH:32])[OH:30])[CH:3]=2
Reactant: COB(OC)OC
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(B(O)O)cc1c32
Reaction time: 1 h

Procedure:
93.7 g (259 mmol) of 6-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine (Br-1) are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., and, after 1 h, 37 ml of trimethyl borate (336 mmol) are added dropwise. The mixture is allowed to come to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed without further purification in the subsequent reaction. The yield is 77 g (235 mmol), corresponding to 91% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(C(=O)COc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)COc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Yield: 45.8 %

Procedure:
To a mixture of 1-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-2-phenoxyethanone (0.048 g, 0.11 mmol), and ethanol (4.0 ml) was added 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was triturated with water, the precipitate was collected by filtration, washed with water, ethanol, and diethyl ether to afford the title compound as a pale yellow solid (0.027 g, 46%); 1H-NMR (500 MHz, DMSO-d6) 3.00 (s, 6H, N(CH3)2), 3.58 (br s) and 3.70 (br s) (8H, 2× piperazine N(CH2)2), 4.92 (s, 2H, COCH2O), 6.95 (m, 3H) and 7.30 (m, 2H) (ArH), 6.82 (d, J=9.02 Hz, 2H) and 8.02 (d, J=8.92 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.19 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.23 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2([C:30]3[N:13]4[CH2:14][CH2:15][S:16][C@:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:19])[CH2:11][C:12]4=[N:33][N:32]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Br)cc2)CC1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
The compound (1.02 g, 3.19 mmol) obtained in Example 4-1) and the compound (0.81 g, 3.19 mmol) obtained in Example 16-3) were dissolved in 1-butanol (5 mL), and the mixture was stirred at 140° C. for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (1.41 g, 85%) in a white solid form.