Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]5[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=5[CH:29]=4)[CH:21]=3)=[C:15]([CH3:42])[CH:14]=2)[CH2:9]1.C(N(CC)CC)C.[C:50]([CH2:52][C:53](Cl)=[O:54])#[N:51].O>ClCCl>[C:50]([CH2:52][C:53]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]([CH3:42])[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]5[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=5[CH:29]=4)[CH:21]=3)=[C:17]([CH3:19])[CH:18]=2)[CH2:9]1)=[O:54])#[N:51]
Reactant: N#CCC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CNC5)cc4C)c3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)CC#N)C5)cc4C)c3)ccc21
Reaction time: 16 h
Yield: 46.2 %

Procedure:
(S)-Methyl 2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2,2,2-trifluoroacetate 14c (150 mg, 0.32 mmol) was dissolved in 10 mL of dichloromethane, followed by addition of triethylamine (65 mg, 0.64 mmol) and the crude 2-cyanoacetyl chloride 16b (49 mg, 0.48 mmol). The reaction solution was stirred for 16 hours. The resulting solution was added with 10 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (5 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the crude title compound (S)-methyl 2-(6-((4′-((1-(2-cyanoacetyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 16c (80 mg, yield 46.2%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:5]([N:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6].[C:33](N1C=CN=C1)(N1C=CN=C1)=[S:34]>C1COCC1.ClCCl.O>[CH2:12]([N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:4]1[CH:16]=[CH:17][C:18]2[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:33](=[S:34])[NH:1][C:2]=2[CH:3]=1)=[O:6])[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(CC(C)C)C(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
A mixture of 3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzamide (1.52 g, 1 eq) and thiocarbonyldiimidazole (0.74 g, 1.2 eq) in THF (30 ml) is stirred at approximately 20° C. for 15 hours. After concentration under reduced pressure at 40° C., the residue obtained is taken up in dichloromethane (80 ml) and water (30 ml). After decanting and extracting, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of a light beige foam (1.2 g; 72% yield).
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:23][N:20]1[CH:21]=[CH:22][C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]4[C:30]([OH:32])=[O:31])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:34][CH:33]=4)[C:11]=3[CH:12]=2)=[N:19]1
Reactant: C1CCNCC1
Reactant: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCCCC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions to Example 152 using piperidine. MS (ESI): mass calcd. for C31H37N5O3, 527.67; m/z found, 528.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.51 (dd, J=8.2, 5.5, 2H), 7.01 (d, J=8.7, 2H), 6.97 (d, J=2.3, 1H), 6.94-6.87 (m, 3H), 6.27 (d, J=2.3, 1H), 5.45-5.34 (m, 2H), 4.99 (s, 2H), 3.83 (s, 3H), 3.63-3.53 (m, 1H), 3.15-3.06 (m, 4H), 2.85-2.76 (m, 1H), 2.43-2.25 (m, 1H), 1.99-1.75 (m, 4H), 1.74-1.63 (m, 5H), 1.63-1.52 (m, 2H), 1.53-1.34 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][CH2:13][OH:14])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31](OS(C)(=O)=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CC(C)=O>[F:15][C:16]([F:45])([F:46])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31]([N:8]2[CH2:7][CH2:6][CH:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:11][CH2:12][CH2:13][OH:14])[CH2:10][CH2:9]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: OCCCN(CCO)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(c1ccccc1)N1CCC(N(CCO)CCCO)CC1

Procedure:
6.4 g of the oil of 4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine prepared according to b) are taken up in 300 ml of acetone, combined with 13.8 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide and 33 ml of triethylamine and refluxed for 6 hours. The mixture is cooled, the solvent is eliminated in vacuo, the residue is stirred into 10% sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, the solvent is eliminated in vacuo and the residue is chromatographed over silica gel with ethyl acetate/methanol/conc. ammonia solution 20:80:1. The uniform fractions according to TLC are combined and freed from the solvents in vacuo. 8.4 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide are obtained as a yellowish-brown oil.
Reaction SMILES: [C:1]([C:3](=[C:25]1[NH:29][C:28]([CH2:30][CH3:31])=[CH:27][S:26]1)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14](NC(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:5]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:6]2[N:5]=[C:4]([C:3](=[C:25]3[NH:29][C:28]([CH2:30][CH3:31])=[CH:27][S:26]3)[C:1]#[N:2])[CH:9]=[CH:8][N:7]=2)[CH2:16][CH2:15]1
Reactant: CCC1=CSC(=C(C#N)c2ccnc(NC3CCN(NC(=O)OC(C)(C)C)CC3)n2)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1=CSC(=C(C#N)c2ccnc(NC3CCNCC3)n2)N1

Procedure:
The Boc protected tert-butyl 4-({4-[cyano(4-ethyl-1,3-thiazol-2(3H)-ylidene)methyl]pyrimidin-2-yl}amino)piperidine-1-carbamate was treated with a solution of 20% TFA in DCM overnight at rt, affording the title compound as a diTFA salt after evaporation of the solvent (52.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>>[O:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(NC1CCOCC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2H-pyran-4-amine (CAN 38041-19-9) as starting materials, MS (LC/MS): 317.1 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([O:13][CH2:14][CH3:15])=[N:11][CH:12]=1.[B:20]([O-])([O-:22])[O-:21]>CCOCC>[CH2:14]([O:13][C:10]1[C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:7]([B:20]([OH:22])[OH:21])=[CH:12][N:11]=1)[CH3:15]
Reactant: [O-]B([O-])[O-]
Reactant: CCOc1ncc(Br)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOc1ncc(B(O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Alternatively, n-butyl lithium (1.6 M solution in hexane, 0.9 mL, 1.43 mmol) was slowly added to a solution of 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine (352 mg, 1.3 mmol) in 2.6 mL anhydrous Et2O at −78° C. under nitrogen. The mixture was kept at −78° C. for 1 hr, and then to this mixture was added triisoporpyl borate (489 mg, 2.6 mmol). The mixture was allowed to warm to ambient temperature overnight. The reaction was quenched by water and the pH was adjusted to 5 by carefully addition of 1N aqueous HCl. Two layers were separated and the aqueous layer was extracted with ethyl acatate three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-ethoxy-3-trifluoromethylpyridine-5-boronic acid as a brown oil (240 mg, 67% yield). The product was used for the next step without purification.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1B(O)O>O1CCOCC1>[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]2=[CH:12][CH:11]=1
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Reactant: OB(O)c1ccccc1Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2nc(-c3ccccc3Cl)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25.0 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-chlorophenylboronic acid (296 mg, 1.89 mmol) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (142 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:39]([O-:41])=[O:40].Cl>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:39]([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)CC1
Agent: Cl
Solvent: CO
Product: Nc1nc(NCCNc2ncc(N3CCNCC3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
1 mmol of tert-butyl 4-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]piperazinecarboxylate was heated to 60° C. 3M HCl in MeOH for one hour and concentrated in vacuo to obtain{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-piperazinylpyrimidin-2-yl]amine.
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:15][NH2:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[NH:16][N:15]=[CH:4]2
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1cccc2cn[nH]c12
Yield: 93 %

Procedure:
A solution of 2-fluoro-3-trifluoromethylbenzaldehyde (5 g, 26 mmol)), hydrazine hydrate (8.3 mL, 260 mmol) and DMAP (3.17 g, 26 mmol.) in 10 mL pyridine was heated at 100° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried with anhydrous sodium sulfate (Na2SO4). The organic phase was concentrated in vacuo to give 4.5 g of product. The crude product was recrystallized from Et2O/hexane to give the title compound (3.6 g, white solid, mp 90° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][NH:33][C:31]([C:28]2[N:20]3[C:19]([CH2:18][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[CH2:1][N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:14][CH:13]=4)=[O:16])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21]3)=[CH:30][CH:29]=2)=[O:32])[CH:36]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3CN3CCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B (0.38 mmol), and pyrrolidine (0.80 mmol) in methanol (5 mL) was added a methanolic solution of sodium cyanoborohydride (0.2 M) and zinc chloride (0.1 M). The mixture was stirred at ambient temperature for 20 hours. The methanol was evaporated and the residue was taken up in chloroform and washed with 1.0 N sodium hydoxide, dried over anhydrous sodium sulfate, and evaporated. The solid was crystallized from ethyl acetate and hexane, m.p. 210-212° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[C:11]([NH2:14])[C:10]=1[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH:24]([CH3:26])[CH3:25])=[N:22][N:23]=2)[N:20]=1.Cl.CO[CH:30](OC)[CH2:31][CH:32](OC)OC.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].CCO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH:24]([CH3:26])[CH3:25])=[N:22][N:23]=3)[N:20]=2)=[C:11]2[N:14]=[CH:30][CH:31]=[CH:32][N:12]2[N:13]=1
Reactant: CC(C)c1nnc2ccc(-c3c(N)n[nH]c3-c3ccc(F)cc3F)nn12
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nn4cccnc34)nn12
Temperature: 80 °C
Yield: 60.4 %

Procedure:
The 5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-3-amine (0.200 g, 0.563 mmol, Example #23) and zinc chloride (0.038 g, 0.281 mmol) were added to EtOH (1 mL). Concentrated HCl (1.0 mL, 33 mmol) was added followed by malonaldehyde bis(dimethyl acetal) (0.111 g, 0.675 mmol). The mixture was heated to about 80° C. for about 15 min then the mixture was poured onto ice and basified with 50% aqueous NaOH. The mixture was extracted with EtOAc then the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel with DCM/MeOH (9:1) as an eluent to give the title compound (0.133 g, 60%): LC/MS (Table 1, Method a) Rt=3.05 min; MS m/z: 392.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (59 mg, 75%), MS (ISP) m/z=314.5 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH2:51])[C@H:47]3[S:46][CH2:45][C:44]=2[CH2:53][O:54][C:55](=[O:57])[CH3:56])=[O:42])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P([O-])([O-])(O)=O.[K+].[K+]>C(Cl)Cl.CN1CCOCC1.O>[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH:51][C:16](=[O:18])[CH2:15][C:13]4[O:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=4)[C@H:47]3[S:46][CH2:45][C:44]=2[CH2:53][O:54][C:55](=[O:57])[CH3:56])=[O:42])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)o1
Agent: CC(C)COC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)o3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1.87 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-furyl)-acetic acid are dissolved in 200 ml of methylene chloride (distilled over phosphorus pentoxide) and 0.80 ml of 4-methylmorpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 1.0 ml of chloroformic acid isobutyl ester is added dropwise whilst keeping the temperature at between -15° C. and -20° C. After 30 minutes, a solution of 2.31 g of 3-acetoxymethyl-7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester is added, after which the mixture is stirred for a further 2 hours at -10° C. and for 8 hours at room temperature. It is then poured out into icecold water, the pH is adjusted to 8.0 with dipotassium hydrogen phosphate and the mixture is repeatedly extracted with methylene chloride. The organic extracts are washed with a saturated aqueous sodium chloride solution and dried over magnesium sulphate, after which the solvent is removed under reduced pressure. 3-Acetoxymethyl-7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-furyl)-acetylamino]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a colourless foam which is directly converted further; thin layer chromatogram (silica gel): Rf=0.84 (system: hexane/ethyl acetate/methanol, 20:40:40).
Reaction SMILES: Cl.CN.[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:22][N:23](C)CCCN=C=NCC>N1C=CC=CC=1>[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:23][CH3:22])=[O:17])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
1.77 g of methylamine hydrochloride was added to a pyridine (60 ml) solution of 3 g of 4-benzyloxybenzoic acid, and 5.04 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to it, and stirred at room temperature. After the reaction, the solvent was evaporated away under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was crystallized from chloroform/hexane and taken out through filtration to obtain 2.272 g of the entitled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]3)=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=1)=[CH:9][C:8]([Br:33])=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:37][C:38](OC(C)(C)C)=[O:39]>CN(C=O)C>[Br:33][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:38](=[O:39])[CH2:37][N:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]5)=[C:15]([C:29]([F:31])([F:30])[F:32])[CH:14]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1CCN(c2ccc(Nc3c(N)cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc(N3CC(=O)Nc4cnc5ccc(Br)cc5c43)cc2C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of compound 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (60 mg, 0.115 mmol, 1 equiv.) in anhydrous DMF (3 mL) at 0° C. was added sodium hydride (60%, 5.0 mg, 0.126 mmol, 1.1 equiv.). After the mixture solution was stirred for 15 minutes, tert-Butyl bromoacetate (19 ┌L, 0.126 mmol, 1.1 equiv.) was added. The resulting mixture was stirred overnight at room temperature under argon. Upon quenching with water, the mixture was concentrated under vacuum, diluted with EtOAc (20 mL), and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1) to afford the desired product 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (61 mg; 94%). LC-MS (M+H): 563.15
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].OS(O)(=O)=O.[NH3:20]>CO>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]1[C:12](=[O:14])[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: N
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 1-Boc-L-azetidine-2-carboxylic acid (10 g), conc. H2SO4 (1 mL) in dry MeOH (200 mL) was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo, the residue was diluted with EA, basified with sat. NaHCO3 solution. The organic extract was washed with water, dried (MgSO4), filtered and concentrated to yield the crude methyl ester as a yellow oil (11 g, 102%). This crude ester was dissolved in dry MeOH (200 mL) and treated with 7M ammonia solution in MeOH (100 mL). The resulting white suspension was stirred at RT for 72 h and filtered off. The filtrate was concentrated in vacuo to give the title compound as a white solid (8.5 g, 92%).