Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:24])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:24][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][CH2:21]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COC1CCN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CCN(CCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2c(Br)cnn2C)CC1
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy)benzenamine (0.024 g, 0.060 mmol) in CH2Cl2 (0.9 mL) was added 3-fluorobenzoyl chloride (0.0086 mL, 0.0714 mmol) and triethylamine (0.011 mL, 0.077 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.027 g, 56%). LCMS m/z (%)=531 (M+H79Br, 94), 533 (M+H81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 7.95 (dd, J=2.1, 8.5 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.79-7.75 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.63-7.57 (m, 1H), 7.45 (dt, J=2.6, 8.3 Hz, 1H), 7.29 (dd, J=3.7, 9.1 Hz, 1H), 4.47-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.69 (s, 3H), 3.27 (s, 3H), 3.53-1.37 (m, 11H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9](N)=[O:10])=[C:5]([N:12]2[CH2:19][CH:18]3[CH:14]([CH2:15][N:16]([CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)[CH2:17]3)[CH2:13]2)[N:4]=1)C.[OH-:31].[Na+].Cl>CCO>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][N:16]1[CH2:17][CH:18]2[CH2:19][N:12]([C:5]3[N:4]=[CH:3][CH:8]=[CH:7][C:6]=3[C:9]([OH:10])=[O:31])[CH2:13][CH:14]2[CH2:15]1
Reactant: [OH-]
Reactant: CCc1ccc(C(N)=O)c(N2CC3CN(Cc4ccc5ccccc5c4)CC3C2)n1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cccnc1N1CC2CN(Cc3ccc4ccccc4c3)CC2C1
Temperature: 80 °C

Procedure:
To a suspension of ethyl 6-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)pyridine-5-carboxamide (0.255 g, 0.63 mmol) in EtOH (2 ml) was added 6M NaOH (2 ml, 12 mmol). The mixture was heated at 80° C. for 90 min and then cooled to r.t. Concentrated HCl was then added until a precipitate formed, and the solid was collected by filtration (240 mg, quant.). The compound was carried onto the next step without characterization.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][NH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c[nH]cc1C
Product: COC(=O)c1c[nH]c(Br)c1C

Procedure:
By a similar operation as in Reference Example 22 and using methyl 4-methyl-1H-pyrrole-3-carboxylate (1.0 g) and N-bromosuccinimide (1.28 g), the title compound was obtained as a pale-yellow solid (yield 489 mg, 31%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][CH:2]=1.BrCC(OC(C)(C)C)=O.[BH4-].[Na+]>>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][N:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: c1cnc2ncccc2c1
Agent: CC(C)(C)OC(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Product: c1cnc2c(c1)CCCN2

Procedure:
Scheme 16 illustrates an alternative method for preparing 79 and related analogues 83. Naphthyridine 75 and 82 are commercially available, known in the literature (e.g., Bioorg. Med. Chem. Lett. (1999) 17:2583-86) or conveniently prepared by a variety of methods familiar to those skilled in the art. Naphthyridine 75 is refluxed with benzyl bromide in acetonitrile to give the quaternary salt 76, which is converted to benzyl protected amine 77 upon treatment with sodium borohydride. The benzyl group in 77 is removed by hydrogenation in the presence of palladium on charcoal to give amine 78, which is transformed to 79 using a standard alkylation reaction. Alternatively, treatment of naphthyridine 75 with tert-butyl bromoacetate followed by reduction of the resultant quaternary salt with NaBH4 gives tetrahydro-naphthyridine 80. Deprotection with HCl provides acid 81, which undergoes BOP coupling with diamine 2 to afford 79. By a similar sequence of reactions, 83 is prepared from 1,7-naphthyridine 82.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10](=[O:13])[NH:11][CH3:12])=[CH:8][N:7]=[C:6]([CH2:14][NH:15][C:16]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])=S)[CH:5]=1)[CH3:2]>O1CCOCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[CH2:1]([O:3][C:4]1[C:9]([C:10](=[O:13])[NH:11][CH3:12])=[CH:8][N:7]2[C:16](=[N:18][C:19](=[O:20])[O:21][CH2:22][CH:23]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:15][CH:14]=[C:6]2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)ncc1C(=O)NC
Agent: O=C([O-])C(F)(F)F
Agent: [Hg+2]
Solvent: C1COCCO1
Product: CCOc1cc2c[nH]c(=NC(=O)OCC3c4ccccc4-c4ccccc43)n2cc1C(=O)NC
Reaction time: 0.17 h

Procedure:
875 mg of N-(4-ethoxy-5-methylcarbamoyl pyridin-2-ylmethyl)-N′-(fluoren-9-ylmethyloxycarbonyl)thiourea (Example 19a, crude product) were dissolved in 25 ml of dioxane and treated at RT with 837 mg (1.96 mmol) of mercury(II) trifluoroacetate. After 10 minutes, the mixture was concentrated and the residue was taken up in DCM. The organic phase was washed three times with 4% strength LiCl solution and once with water, dried with MgSO4 and concentrated in a rotary evaporator. The crude product thus obtained (590 mg) was reacted further without further purification.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[Cl:12][C:13]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1cccc(C(F)(F)F)c1Cl

Procedure:
The title compound, yellow solid, MS: m/e=361.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-chloro-3-trifluoromethylbenzoic acid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCl>[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc(CC2CCCN2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(C1CC1)N1CCCC1Cc1ccc(Cl)cc1
Yield: 67.5 %

Procedure:
Add (dropwise, at 0° to 8°) 5.2 g of cyclopropanecarboxylic acid chloride in 10 ml of dichloromethane to 10 g of 2-(4-chlorobenzyl)pyrrolidine and 6.2 g of triethylamine. Stir the thus-prepared reaction mixture for a further 2 hours at 0°. Add water thereto. Separate off the organic phase and extract it with dichloromethane. Combine the organic phases and wash them with dilute hydrochloric acid and sodium carbonate solution. Dry the washed material over sodium sulfate. Evaporate off the solvent from the dried material, and then distil the oily residue to obtain the title compound (8.85 g) in the form of oil (b.p. 135° to 137° at 0.005 mm Hg), which solidifies to a crystalline mass of m.p. 62° to 64°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:9][CH2:8][CH:7]([OH:10])[CH2:6][O:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[O:2][CH3:1])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1OCC(O)CO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccccc1OCC(O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A solution of 3-(2-methoxy-phenoxy)-propane-1,2-diol (4.7 g) in pyridine, cooled at 5°-10° C., is treated under stirring with a solution of p-toluensulphonylchloride (4.5 g) in benzene (70 ml). The reaction mixture is stirred overnight at room temperature, then it is washed with 2N HCl (3×100 ml) and with water, dried on Na2SO4 and evaporated to dryness in vacuum. The oily residue is purified by column chromatography (silica gel 230-400 mesh hexane/AcOEt=3/1) to yield 5 g of 3-(2-methoxy-phenoxy)-2-hydroxy-1-propyl p-toluensulphonate (oil, NMR (--CDCl3):δ=2,4 3H (s) CH3SO2 ; δ=3,75-4,4 5H (m) OCH3 +OCH2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.F[P-](F)(F)(F)(F)F.[N:21]1([O:30][C:31](N(C)C)=[N+](C)C)[C:25]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:21]([O:30][CH3:31])[CH3:25])=[O:13])[NH:6]2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2c(Cl)cccc2[nH]1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
A mixture of 4-chloro-1H-indole-2-carboxylic acid (from Ryan Scientific, 1.0 g, 5.1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.9 g, 7.7 mmol) and triethylamine (3.6 mL, 26 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.75 g, 7.7 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and then extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-35% EtOAc in hexane) to give the desired product (0.35 g, 29%). LCMS calculated for C11H12ClN2O2(M+H)+: m/z=239.1. Found: 239.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([N:27]([CH:36]([CH3:38])[CH3:37])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:26]>CN(C)C=O>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH:16][CH2:24][C:25]([N:27]([CH:36]([CH3:38])[CH3:37])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:26])=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Nc1cc(F)c(F)cc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2cc(F)c(F)cc2Nc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A mixture of 3.004 g of 4,5-difluoro-N-phenyl-benzene-1,2-diamine (J. Gen. Chem. USSR (Engl. Transl.), 1964, 34), 1.910 g of potassium carbonate (13.82 mmol, 1.0 equiv), and 3.956 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (13.82 mmol, 1.0 equiv) in 20 mL of dimethylformamide is stirred under nitrogen at ambient temperature for 16 h. An additional 3.00 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (10.5 mmol, 0.75 equiv) is added and the reaction is heated at 50° C. for 2 h. The mixture is cooled to ambient temperature and then partitioned between diethyl ether and 1:1 water/saturated aqueous brine. The layers were separated and the aqueous layer is back-extracted twice with diethyl ether. The ether layers were combined, washed with saturated aqueous brine, dried over anhydrous sodium sulfate and then evaporated in vacuo to a residue. The residue is purified on flash grade silica gel using 10-20% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo and dried under vacuum to provide 5.62 g of 2-(4,5-Difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a solid: Low resolution MS (FAB)m/e 425 (M+); TLC Rf =0.43 (ethyl acetate/hexane 3:7).
Reaction SMILES: [O:1]1[CH2:4][C:3]([CH2:7][NH2:8])([CH2:5][NH2:6])[CH2:2]1.C(N(CC)CC)C.[Cl:16][C:17]1[N:26]=[C:25](Cl)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=2)[N:18]=1>ClCCl.O>[NH2:6][CH2:5][C:3]1([CH2:7][NH:8][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=3)[N:18]=[C:17]([Cl:16])[N:26]=2)[CH2:4][O:1][CH2:2]1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC1(CN)COC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2nc(Cl)nc(NCC3(CN)COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a mixture of oxetane-3,3-diyldimethanamine (1.16 g, 10.0 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added dropwise of a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL). After being stirred at room temperature overnight, the resulting mixture was diluted with water (50 mL), and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 300 mg of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[C:6]([OH:8])[CH:7]=1.C(OC(=O)[N:25]([S:31]([C:34]1[CH:39]=[C:38]([Cl:40])[C:37](F)=[CH:36][C:35]=1[F:42])(=[O:33])=[O:32])[C:26]1[N:27]=[CH:28][S:29][CH:30]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O.O>[Cl:40][C:38]1[C:37]([O:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:15]([F:16])([F:18])[F:17])=[CH:4][C:5]=2[C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:36][C:35]([F:42])=[C:34]([S:31]([NH:25][C:26]2[N:27]=[CH:28][S:29][CH:30]=2)(=[O:32])=[O:33])[CH:39]=1
Reactant: Oc1cc(F)c(C(F)(F)F)cc1-c1ccnnc1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cc(F)c(C(F)(F)F)cc2-c2ccnnc2)cc1F
Temperature: 75 °C

Procedure:
A mixture of 5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 9, 2.81 g, 10.9 mmol), tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 5.59 g, 13.6 mmol) and potassium carbonate (4.51 g, 32.6 mmol) in dimethylsulfoxide (20 mL) was heated at 75° C. for 24 hours. The reaction mixture was cooled to ambient temperature, diluted with water, neutralized with saturated aqueous ammonium chloride, then extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via automated silica gel flash chromatography using two runs, (10% to 100% ethyl acetate in hexanes gradient elution for run 1, and 0% to 10% methanol in dichloromethane gradient elution for run 2) to afford the title compound as a brown solid. (2.42 g, 41%)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:38]3=[N:39][CH:40]=[N:41][C:42](Cl)=[C:37]3[CH:36]=[N:35]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[C:38]3=[N:39][CH:40]=[N:41][C:42]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=5)[CH2:8][CH2:9]4)=[C:37]3[CH:36]=[N:35]2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CCc5cc(S(C)(=O)=O)ccc54)ncnc32)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
5-(Methylsulfonyl)-indoline (Matrix Scientific, Columbia, S.C., USA; 30 mg, 0.15 mmol) and triethylamine (70 μL, 0.5 mmol) were added to a solution of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 45 mg, 0.133 mmol) in tetrahydrofuran (1 mL). The mixture was heated to reflux. No reaction had occurred after 2 h. The volatiles were evaporated. Dimethylformamide (1 mL) and cesium carbonate (250 mg, 0.77 mmol) were added. The mixture was heated at 70° C. overnight, then poured into saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic extracts were washed twice with water and once with brine, dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography eluting with ethyl acetate to give 4-[4-(5-methanesulfonyl-2,3-dihydro-indol-1-yl)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (14 mg, 21%) as an off-white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:38]/[O:39][CH3:40])/[C:15]([NH:17][C@@H:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:38]/[O:39][CH3:40])/[C:15]([NH:17][C@@H:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To 50 ml of trifluoroacetic acid is added 13 g of 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid with stirring under ice-cooling. The cooling bath is removed and stirring is continued for 30 minutes. Trifluoroacetic acid is evaporated off under reduced pressure. To the residue is added 100 ml of ethyl acetate and the ethyl acetate is removed under reduced pressure. To the residue is added 100 ml of diethyl ether. Trituration and filtration of the resulting powder give 10 g of the above-identified compound.
Reaction SMILES: [N:1]1C=CC=CC=1C1C(=O)NN=CC=1.NN.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[N:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.O.NN>C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:24]1[C:25](=[O:28])[NH:26][N:27]=[C:22]([C:19]2[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=2)[CH:23]=1
Reactant: O=c1[nH]nccc1-c1ccccn1
Reactant: Oc1ccc(-c2ccncc2)nn1
Agent: NN
Agent: O=C([O-])[O-]
Agent: O=c1ccc(-c2ccncc2)n[nH]1
Solvent: O
Product: Nc1cc(-c2ccncc2)n[nH]c1=O
Yield: 69 %

Procedure:
G-2. 4-Amino-6-(4-pyridinyl-3(2H)-pyridazinone--The following procedure describes the preparation of the entitled compound by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-puridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixture containing 10 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 70 ml. of hydrazine hydrate was heated on a steam bath for 3 days and the excess hydrazine distilled off in vacuo. The remaining residue was heated with about 300 ml. of methanol and the solid was collected by filtration. The solid was combined with the corresponding solid obtained from another run starting with 15.7 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21 ml. of hydrazine hydrate and the combined solids were dissolved in aqueous potassium carbonate solution and reprecipitated by addition of acetic acid. The precipitate was dried for 9 hours at 40° C. over P2O5 and then overnight at 80° C. After its NMR spectrum had shown the solid still to contain acetic acid, it was next dried in a vacuum oven at 80° C. for 2 days to yield 18.2 g. (69% yield) of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.Cl.[CH:20]1([N:23]([CH2:29][CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH:20]1[CH2:22][CH2:21]1)[CH2:29][CH3:30])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN(CCCCN)C1CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)C1CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine, N1-cyclopropyl-N1-ethylbutane-1,4-diamine HCl salt (Step 2) and diisopropyethylamine (4 eq), the title compound was obtained; MS (Found M+1=398).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.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(#N)C>[CH3:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[N:7]=2)[CH:10]=1)=[O:29]
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(-c4cncnc4)n3)c3ccccc3c2=O)cc1C
Temperature: 75 °C
Reaction time: 18 h

Procedure:
90 mg (0.2 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one 4 mm, 50 mg (0.40 mmol) of pyrimidin-5-boronic acid, 18.3 mg (0.02 mmol) of Pd2(dba)3, 21 mg (0.08 mmol) of triphenylphosphine were dissolved in 2 mL of tetrahydrofuran. To the resultant solution was added 0.5 mL (1.0 mmol) of 2N Na2CO3 aqueous solution and the mixture was stirred at 75° C. for 18 h. The reaction mixture was quenched by pouring into a container having 20 mL of water. The crude product precipitated out of solution and was isolated by filtration. The crude product 4oo was purified by flash chromatography to yield 14 mg of colorless a solid: LC-MSD, m/z for C28H22N4O2, [M+H]+=447.5, [M+2H]+=448.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.055 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (d, 6H), 5.56 (s, 2H), 7.17 (d, 1H), 7.36-7.48 (m, 2H), 7.52-7.66 (m, 3H), 7.72 (d, 1H), 7.81 (t, 1H), 8.37 (s, 1H), 8.42-8.50 (m, 1H), 9.22-9.32 (m, 3H).