Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>[Pt].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Yield: 99.3 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1) (21.62 g, 0.0644 mol), triethylamine (40 mL) and 5% Pt/C catalyst (21 g, 56% w/w water) in MeOH (400 mL) was hydrogenated at room temperature and atmospheric pressure overnight. The catalyst was removed by filtration and washed with further MeOH. The filtrate was concentrated, re-dissolved in DCM (200 mL) and washed with 2M NaOH solution. The aqueous wash was re-extracted with DCM (×2, 100 mL) and all organic phases were combined, washed with brine, dried and concentrated to give the title compound (19.53 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[S:45](Cl)([CH3:48])(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([S:45]([CH3:48])(=[O:47])=[O:46])[CH2:30][CH2:31]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.397 mmol) in DCM (5 mL), Et3N (0.06 g, 0.596 mmol) and mesyl chloride (0.046 g, 0.403 mmol) were added at 0° C. and stirred it at room temperature for 2 h. After completion, reaction was quenched with ice-water. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound. LCMS: 582.30 (M+1)+; HPLC: 92.74% (@ 254 nm) (Rt; 5.006); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.86 (bs, 1H), 8.87 (t, 1H, J=4.8 Hz), 8.34 (s, 1H), 7.90 (s, 1H), 6.93 (s, 1H), 5.90 (s, 1H), 5.23-5.20 (m, 1H), 4.39 (d, 2H, J=4.4 Hz), 4.08 (bs, 2H), 3.80 (bs, 2H), 3.72 (d, 2H, J=11.60 Hz), 3.30 (bs, 2H), 3.15 (d, 2H, J=15.60 Hz), 2.93 (s, 3H), 2.84-2.76 (m, 2H), 2.27 (m, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 1.81-1.73 (m, 2H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)(=O)[CH3:11].[OH-].[K+]>CO>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[C:10]1[CH:11]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)c1nccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1cnc2nc(-c3nccs3)ccc2c1
Reaction time: 3 h
Yield: 46.5 %

Procedure:
2-Aminonicotinaldehyde (1.5 g, 12.3 mmol) and 2-acetylthiazole (1.64 g, 12.9 mmol) are dissolved in 12 ml of MeOH and the mixture is treated with 1.5 ml of 40% KOH. After 3 h, the reaction is complete and the mixture is poured onto water. The solid which is deposited is filtered off with suction, washed and dried. 1.22 g (yield 46%) of the desired product are obtained. M.p. 160°-165° C.
Reaction SMILES: Br.[CH3:2][N:3]1[N:7]=[N:6][C:5]([C:8]2[CH2:9][NH:10][CH2:11][CH2:12][CH:13]=2)=[N:4]1.[CH:14](O)=O>C=O>[CH3:2][N:3]1[N:7]=[N:6][C:5]([C:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=2)=[N:4]1
Reactant: Cn1nnc(C2=CCCNC2)n1
Reactant: O=CO
Agent: Br
Agent: C=O
Product: CN1CCC=C(c2nnn(C)n2)C1
Yield: 74 %

Procedure:
A solution of 8 (0.70 g, 0.0028 mol) in formic acid (20 ml) and 35% formaldehyde (7 ml) was refluxed overnight. The solution was evaporated in vacuo, and the residue was taken up in ether (20 ml) and 28% sodium hydroxide (20 ml). The phases were separated, and the aqueous phase was extracted three times with dichloromethane (20 ml). The combined organic phases were washed four times with saturated sodium chloride solution (20 ml). The organic phase was dried over magnesium sulphate and evaporated in vacuo yielding 0.60 g of crude 10. Crystallization from ether - light petroleum gave 0.37 g (0.0021 mol, 74%) of title compound, M.P. 86°-87° C. Anal. (C8H13N5) C, H, N.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14]COCC)[C:7]=1[CH3:19])C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([CH3:19])[C:8]=1[OH:14]
Reactant: CCOCOc1ccc(OC)c(OCOCC)c1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(C)c1O
Yield: 98 %

Procedure:
A solution of 5a (910 mg, 3.37 mmol) in MeOH (28.0 mL) at room temperature was treated dropwise with 3 M HCl (9.00 mL, 26.9 mmol), then heated to reflux for one hour. Water (30 mL) was added and the solution was extracted with EtOAc (3×30 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 6a as a red amorphous solid (509 mg, 98%): 1H NMR (Acetone-d6, 500 MHz) 7.68 (s, 1H), 7.24 (s, 1H), 6.60 (d, J=11 Hz, 1H), 6.29 (d, J=11 Hz, 1H), 3.74 (s, 3H), 2.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 144.7, 142.1, 139.7, 115.6, 110.2, 108.6, 55.6, 7.6; IR (film) νmax 3583, 2920, 2359, 1616, 1259, 1090, 1020, 798 cm−1.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Cc1cc(C2=CCCCC2)ccc1C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C2CCCCC2)ccc1C(=O)O
Yield: 86.2 %

Procedure:
To a solution of 4-cyclohexenyl-2-methylbenzoic acid (2.61 g) in ethanol (30 ml) and ethyl acetate (30 ml) is added 5% palladium-carbon (0.4 g), and the mixture is stirred at room temperature under atmospheric pressure of hydrogen gas for 30 minutes. The palladium-carbon is removed by filtration through celite, and the filtrate is evaporated to remove the solvent. The precipitated crystals are collected by filtration, crystallized from acetone/n-hexane, and washed to give 4-cyclohexyl-2-methylbenzoic acid (2.27 g) as white powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccc(C(F)(F)F)cc2)n1
Yield: 60.1 %

Procedure:
The title compound was prepared from 4-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give to give 3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.36 g, 4.81 mmol, 60%). 1H NMR (300 MHz, DMSO-d6) δ 7.81 (d, 2H), 7.80 (d, 2H), 5.44 (s, 3H), 1.22 (s, 9H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27](OCC)[O:28]CC)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1563 g) in acetone (10 ml) was added 6N-hydrochloric acid (2.5 ml) and stirred at room temperature for 30 minutes. After removing acetone, water was added to the residue and neutralized with aqueous solution of sodium bicarbonate. The precipitated solid was collected by filtration, washed with water and then dried to give yellowish powder to diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (0.9407 g). The product was recrystallized for a mixture of ethanol and n-hexane to give the pure product, m.p. 101°to 103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:21]([N:23]([CH2:33][C:34]1[C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[S:37][CH:38]=1)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:21]([N:23]([CH2:33][C:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[S:37][CH:38]=2)[C@@H:24]([CH3:32])[CH:25]([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C(O)C.Cl>C1(C)C=CC=CC=1>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: CCc1ccc(-c2ccc(N(C(C)=O)c3ccc(C)cc3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(Nc3ccc(C)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 19.96 g of the thus obtained N-acetyl-N-(4-methylphenyl)-4'-ethyl-[1,1'-biphenyl]-4-amine were added 150 ml of ethanol and 150 ml of concentrated hydrochloric acid. The reaction mixture was refluxed with stirring for 7 hours and then added to 1 l of ice water. The reaction mixture was then extracted with toluene and the obtained organic portion was washed with water two times, with a saturated aqueous solution of sodium hydrogencarbonate one time, and then with water two times, and dried by use of magnesium sulfate, and condedsed under reduced pressure, whereby brown crystals were obtained. The thus obtained product was subjected to a silica gel column chromatography by use of toluene as an eluent, and recrystallized from a mixed solvent of n-hexane and toluene, whereby 4'-ethyl-N-(4-methylphenyl)-[1,1'-biphenyl]-4-amine (Aminobiphenyl Compound No. 2-62 in Table 3) was obtained in the form of colorless plates with a yield of 15.84 g (91.0%). The melting point of the product was 132.5° C. to 133.0° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]([CH3:14])[C:6](=[O:13])[N:7]2[CH3:12].[F-].[Cs+].[CH2:18](B1OC(C)(C)C(C)(C)O1)[CH:19]=[CH2:20]>O1CCOCC1.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>[CH2:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]([CH3:14])[C:6](=[O:13])[N:7]2[CH3:12])[CH:19]=[CH2:18]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c2c(I)cccc2n(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCc1cccc2c1c(=O)n(C)c(=O)n2C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a stirred solution of Step 4 intermediate (40 g, 126 mmol) in 1,4-dioxane (1.3 lit) was added cesium fluoride (38.3 g, 252 mmol) and allylboronic acid pinacol ester (42.5 ml, 225 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (14.46 g, 12 mmol) catalyst was added and the mixture was stirred at 100° C. for 20 h under nitrogen atmosphere. The mixture was diluted with water (500 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were concentrated and the residue obtained was purified by silica gel column chromatography to give 26.5 g of the product as an off-white solid; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.54 (t, J=7.8, 1H); 7.08 (t, J=6.9, 2H); 6.18-6.00 (m, 1H); 5.06-4.95 (m, 2H); 4.04 (d, J=6.3, 2H); 3.60 (s, 3H); 3.45 (s, 3H). MS (m/z): 231.37 ([M+H]+).
Reaction SMILES: NCCC[NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7].FC1C=C[C:35]([C:38]2C(C3C=C4C(=CC=3)N(C(N3C5C(=CC(C6C(C7C=CC(F)=C(C)C=7)=NC=CC=6)=CC=5)C=N3)=O)N=C4)=CC=C[N:39]=2)=CC=1C>>[NH2:39][CH2:38][CH2:35][NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7]
Reactant: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)n3ncc4cc(-c5cccnc5-c5ccc(F)c(C)c5)ccc43)c2)ccc1F
Reactant: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)NCCCN)c2)ccc1F
Product: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)NCCN)c2)ccc1F

Procedure:
N-(3-Aminopropyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide (Compound 640).LCMS: rt 3.41 min (A), purity 99%, MS (m/e) 404 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(-c2ccc3ccc(N)nc3n2)c1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2ccc3ccc(NC(=O)c4cccc(Br)c4)nc3n2)c1
Temperature: 4 °C
Yield: 13.2 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (4 g), N,N'-carbonyldiimidazole (3.2 g) and 2-amino-7-(3-methoxyphenyl)-1,8-naphthyridine (3.5 g). The product obtained by precipitation in water (4 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (200 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×3 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-[7-(3-Methoxyphenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (0.8 g), m.p. 104° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([O:17][CH3:18])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:18][O:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@@H]1CNC[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-methoxypyrrolidine-1-carboxylate (2.90 g, 8.28 mmol) in DCM (20 mL) was added 4 N HCl (20.69 mL, 82.76 mmol) in dioxane. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. Saturated bicarbonate (20 mL) and DCM (50 mL) were added. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure to give benzyl (3R,4R)-4-methoxypyrrolidin-3-ylcarbamate (2.0 g, 96.6%) as oil.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[O:22][C:12]([CH:13](CC([O-])=O)CC([O-])=O)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(O)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[NH:33][N:32]=[C:31]2[C:39]([NH:41][NH2:42])=[O:40]>CN(C)C=O>[N+:6]([C:9]1[O:22][C:12]([CH:13]=[N:42][NH:41][C:39]([C:31]2[C:30]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=3)[NH:33][N:32]=2)=[O:40])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C([O-])CC(CC(=O)[O-])c1ccc([N+](=O)[O-])o1
Reactant: COc1cc2[nH]nc(C(=O)NN)c2cc1OC
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2[nH]nc(C(=O)NN=Cc3ccc([N+](=O)[O-])o3)c2cc1OC
Reaction time: 24 h
Yield: 70 %

Procedure:
5 ml. of concentrated sulfuric acid are added dropwise to the suspension of 6 g. of 5-nitrofurfurylidenediacetate in 100 ml. of ethanol, and the mixture is stirred for 10 to 30 minutes at 50°C. Thereafter a solution of 6 g. of 5,6-dimethoxyindazole-3-carboxylic acid hydrazide in 100 ml. of dimethylformamide is added, and the mixture is allowed to stand at room temperature for 24 hours. 6.3 g. (70 %) of 5,6-dimethoxyindazole-3-carboxylic acid-(5'-nitro-furfurylidene)-hydrazide are obtained; m.p.: 334°C. This compound is identical with Compund 26 of Table 5.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1)(=[O:33])=[O:32])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(OCCN)cc(C(=O)OCC)n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc(C(=O)OCC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 957 mg of diethyl 4-(2-amino-ethoxy)-pyridine-2,6-dicarboxylate monohydrochloride in 30 ml of DCM and 734 μl of pyridine, precooled to about 5° C., was added 798 mg of 2-nitrobenzenesulfonyl chloride. The mixture was warmed to room temperature and stirred for 2 hours. A further 244 μl of pyridine and 665 mg of 2-nitrobenzenesulfonyl chloride were then added thereto and stirring was continued for 15 hours. The mixture was washed with 25 ml of water and the aqueous phase was extracted 2× with 25 ml of DCM. The organic phases were combined, dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica (Merck EasyVarioPrep 150 g column, Si60 15-40 μm), using a gradient of 0 to 10% EtOAc in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 960 mg of diethyl 4-[2-(2-nitro-benzenesulfonylamino)-ethoxy]-pyridine-2,6-dicarboxylate were obtained. 1H NMR (400 MHz, DMSO-d6): 1.35 (t, J=7.2 Hz, 6H); 3.41 (t, J=5.2 Hz, 2H); 4.22 (t, J=5.2 Hz, 2H); 4.39 (q, J=7.2 Hz, 4H); 7.50 (s, 2H); 7.80 (m, 2H); 7.92 (m, 1H); 8.04 (m, 2H); 8.40 (m, 1H). LC/MS (C): tr=3.50 min; [M+H]+: m/z 468.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH:26](Br)([CH3:28])[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]=[C:14]2[O:23][CH:26]([CH3:28])[CH3:27])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cc(-n2c(OC(C)C)nc3c(c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate with sodium hydride and isopropyl bromide in hexamethyl-phosphoric acid triamide there is obtained ethyl 2-chloro-5-(4,5,6,7-tetrahydro-2-isopropoxy-4-oxo-3H -cyclopenta[d]pyrimidin-3-yl)-benzoate. 1H-NMR (CDCl3, 400 MHz): 7.69 ppm (d,1H), 7.54 ppm (d,1H), 7.23 ppm (q,1H), 5.30 ppm (m,1H), 4.38 ppm (q,2H), 2.79 ppm (m,4H). 2.09 ppm (m,2H), 1.38 ppm (t,3H), 1.22 ppm (d,6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH:34]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][C:45]=3[F:46])[N:42]=[CH:41][CH:40]=[CH:39]4)[CH3:35])=[CH:32][N:33]=2)[N:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:46][C:45]1[CH:44]=[C:43]2[C:38]([CH:39]=[CH:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:14]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1)[CH3:35]
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 72.5 mg, 0.225 mmol), (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-7-fluoro-quinoline (Stage 255.2, 49 mg, 0.15 mmol), and 2 M K2CO3 (0.203 mL) in DME (1 mL) stirred at 80-90° C. under argon atmosphere was added PdCl2(PPh3)2 (3.2 mg). After 1.5 h and cooling to rt the RM was taken-up in DCM and water, the aqueous phase was extracted with DCM, the combined organic layers were dried over MgSO4, filtered, evaporated to dryness and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=100:0->80:20) to afford the title compound as a white solid (tR 4.14 min (conditions 3), MH+=487.2).