Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(Cl)CCl>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])=[CH:25][CH:24]=1)(=[O:27])=[O:28])=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(S(N)(=O)=O)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(=O)(=O)NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of 2,4-dichlorobenzoic acid (1.25 eq) in dry dichloromethane (10 mL/mmol), 4-(tert-butyl-dimethylsiloxy)phenylsulfonamide (1.0 eq) is added in one portion followed by EDC (1.25–1.5 eq) and finally, NN-dimethyl-4-aminopyridine (1.2 equiv). The mixture is vigorously stirred under nitrogen for 16 hr, concentrated under reduced pressure, and the residue partitioned between ethyl acetate and water. The organic layer is washed with 1N hydrochloric acid (4 times, 20 mL/mmol), then the combined aqueous phases extracted with ethyl acetate (twice, 20 mL/mmol). The combined organic layers are finally washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography or crystallization if necessary or desired. ESI-MS m/e 458.0 (M+−H; 460.0 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:20][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=1)[N:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:17]2=[O:18]
Reactant: Cc1ncccc1-n1c(C=O)nc2ccc(F)cc2c1=O
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ncccc1-n1c(CNc2cccc(CN3CCCC3)c2)nc2ccc(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.158 g, 0.56 mmol), 3-pyrrolidin-1-ylmethylaniline (0.050 g, 0.28 mmol), and acetic acid (0.16 mL, 2.8 mmol) in dichloroethane (15 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.297 g, 1.4 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (35 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (50 mL), nil; (75 mL), unweighed impurity; (50 mL), unweighed 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (50 mL), unweighed mixed fraction; (100 mL), 0.031 g (25%) of 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a yellow foam which had: 1H NMR δ 8.72 (d, J=5 Hz, 1 H), 7.92 (dd, J=3, 8 Hz, 1 H), 7.82 (dd, J=5, 9 Hz, 1 H), 7.58-7.52 (m, 2 H), 7.39 (dd, J=5, 8 Hz, 1 H), 7.08 (t, J=8 Hz, 1 H), 6.67-6.64 (m, 2 H), 6.37 (d, J=8 Hz, 1 H), 5.10 (s, 1 H), 3.90 (dd, J=4.5, 17 Hz, 1 H), 3.70 (dd, J=5, 17 Hz, 1 H), 3.56 (ABq, Δv1-3=21 Hz, J=12.5 Hz, 2 H), 2.54 (s, 4 H), 2.36 (s, 3 H), 1.78 (s, 4 H); APCI MS m/z=444 (P+1).
Reaction SMILES: CCCCCC[O:7][C:8](/[N:10]=[C:11](\N)/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:9].CS(O)(=O)=O.[OH2:52]>>[CH2:14]([O:7][C:8]([NH:10][C:11]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:22]=[CH:23][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:25][C:26]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:52])=[O:9])[CH2:13][CH2:12][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Reactant: O
Agent: CS(=O)(=O)O
Product: CCCCCCOC(=O)NC(=O)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
32 g of dabigatran etexilate were suspended in 320 mL of deionized water. 5.4 g of methanesulfonic acid were added. The reaction mixture was heated to 50° C. and stirred at this temperature for 72 hours. The resulting mixture was filtered, and the solid was dried under vacuum. The solid was purified by column chromatography, eluting with ethyl acetate:methanol (15:1 v/v) mixture. After solvent evaporation of the selected fractions containing the desired compound, 15 g of ethyl 3-{[(2-{[(4-{[({hexyloxy}carbonyl)amino]carbonyl}-phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]1[NH:51][CH2:50][CH2:49][N:48]2[CH2:52][CH2:53][CH2:54][C@H:47]12>CN(C)C(=O)C.CC1CCCO1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][S:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:51]2[CH2:50][CH2:49][N:48]3[CH2:52][CH2:53][CH2:54][C@@H:47]3[CH2:46]2)=[O:18])[CH:14]=1)(=[O:12])=[O:11]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid (0.96 g, 3.06 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.28 g, 3.37 mmol) in N,N-dimethylacetamide (7.4 mL) and 2-methyltetrahydrofuran (22 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.54 g, 4.28 mmol). The reaction was stirred at ambient temperature for 5.5 hours, and then it was diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×15 mL), and then it was concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1.O>CN(C)C=O.CC(C)=O.ClCCl>[CH2:38]([O:37][C:35]([C:33]1[O:34][C:30]([CH2:29][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:31][CH:32]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonyl-piperidin-4-yl)amine (10.94 g, 37.9 mmol), sodium carbonate (6.03 g, 57 mmol), and ethyl 5-chloromethyl-2-furoate (12.88 g, 68.3 mmol) in dimethylformamide (115 mL). Heat at about 70° C. After 18 hours, cool the reaction mixture and pour into water. Extract four times with 2/1 ethyl acetate/toluene. Combine the organic layers and extract with brine. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 20% acetone/dichloromethane. Combine the product containing fractions and evaporate in in vacuo to give a residue. Triturate the residue with diethyl ether to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give (1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine. Recrystallization of an analytical sample (0.3 g) from ethyl acetate/hexane (about 1 mL/4 mL) gives (1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: mp; 133-135° C. Elemental Analysis calculated for C23H28N4O5: C 62.71; H 6.41; N 12.72; Found: C 62.69; H 6.29; N 12.66.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=O)[CH3:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH3:15])=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1ccccc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccccc1Br
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
To a suspension of methyltriphenyl phosphonium bromide (108 g, 303 mmol) in THF (750 mL) at room temperature was added KOtBu (112.24 g, 303 mmol) in portions. After being stirred for 5 min, the reaction mixture was treated with 2′bromoacetophenone (50.3 g, 253 mmol). The reaction mixture was stirred for 3 hrs at room temperature then quenched with saturated ammonium chloride. Extracted 3× with Et2O and the combined organic layers were washed with brine, dried over MgSO4 and evaporated under vacuum. Purified by silica gel chromatography (100% petroleum ether) to give 43.8 g (88%) of 1-bromo-2-(prop-1-en-2-yl)benzene as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]([C:57]1[CH:58]=[C:59]([CH:61]=[CH:62][CH:63]=1)[NH2:60])([CH3:56])[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:60][C:59]3[CH:61]=[CH:62][CH:63]=[C:57]([CH:54]([CH3:56])[CH3:55])[CH:58]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CC(C)c1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 37 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and HBTU (250 mg, 0.66 mmol) in 6.0 mL DMF was stirred at room temperature for 3 minutes, briefly warmed to approx. 50° C. to dissolve solids, stirred an additional 10 minutes at room temperature, then 3-isopropylaniline (0.127 mL, 0.90 mmol) added and the reaction heated at 65° C. After 2 hours the mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was chromatographed eluting with EtOAc/MeOH. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove any silica gel impurity and then recrystallized from EtOAc to give the title compound as a pale yellow-beige solid (86 mg, 37%). 1H NMR (DMSO-d6) δ: 10.09 (s, 1H), 8.13 (s, 1H), 7.64-7.66 (m, 1H), 7.58-7.63 (m, 1H), 7.50-7.53 (m, 1H), 7.32-7.40 (m, 2H), 7.18-7.29 (m, 2H), 6.96-7.01 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.88 (spt, J=7.0 Hz, 1H), 2.77 (t, J=5.9 Hz, 2H), 1.22 (d, J=7.0 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[CH:37]12[N:43]([C:44](=O)[CH2:45]Br)[CH:40]([CH2:41][CH2:42]1)[CH2:39][CH2:38]2>>[CH:37]12[N:43]([CH2:44][CH2:45][O:1][C:2]3[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=4[CH:18]4[CH2:27][CH2:26][C:25]5[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=5[CH2:19]4)=[CH:4][CH:3]=3)[CH:40]([CH2:41][CH2:42]1)[CH2:39][CH2:38]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CBr)N1C2CCC1CC2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 57.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH2:17])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[C:30]([C:34]1[C:35]([Cl:43])=[C:36]([C:40](O)=[O:41])[N:37]([CH3:39])[N:38]=1)([CH3:33])([CH3:32])[CH3:31].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH:17][C:40]([C:36]3[N:37]([CH3:39])[N:38]=[C:34]([C:30]([CH3:32])([CH3:31])[CH3:33])[C:35]=3[Cl:43])=[O:41])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[N:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(N)c2[N+](=O)[O-])CC1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(NC(=O)c3c(Cl)c(C(C)(C)C)nn3C)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (240 mg, 0.630 mmol, prepared as described in the previous step) in THF (10 mL) was treated with NaH (75.6 mg, 1.89 mmol, 60% dispersion in mineral oil) at room temperature for 1 h. At the same time, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (164 mg, 0.756 mmol, prepared as described in Example B) in DCM (10 mL) was treated with oxalyl chloride (66.0 μL, 0.756 mmol) and DMF (2 drops) at room temperature for 1 h. The resulting mixture was concentrated in vacuo, taken up in THF (6 mL), and added to the sodium anilide solution at room temperature. The solution was stirred at room temperature for 30 min, quenched with saturated aqueous NH4Cl (20 mL), and extracted three times with EtOAc (25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 3:2 v/v for 5 min, then 3:2 to 4:1 v/v over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as an orange solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C26H29ClF3N7O3: 580.2 (M+H). Measured: 580.2.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:5][CH:4]=1)=[O:2].Cl.C(OCC)C>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1ncc(C=O)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 137.1 %

Procedure:
To a solution of material from Example 60 (400 mg, 1.402 mmol) in CH2Cl2 (75 mL) is added HCl, 1.0M in diethyl ether (25 mL, 25.00 mmol) and the resulting pale yellow solution is stirred at room temp for 18 h. The solvent is removed in vacuo to give 356 mg (98%) of the title compound as a bis HCl salt by weight. LC/MS (Condition A): ret. T=0.522 min, (M+H)+ 186.11.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16]1>CO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:21]1[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
A solution of 5-nitroindole (38) (0.2 g, 1.233 mmol) in dry methanol (5 mL) was treated with KOH (0.56 g) at room temperature. After stifling for 10 min., 1,4-cyclohexanedione monoethylene ketal (0.48 g, 3.083 mmol) was added and the resulting solution was refluxed for 36 h. The reaction was brought to room temperature and solvent was evaporated. The crude product was diluted with water (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by flash-column chromatography (ethyla acetate) to obtain compound 78 (0.25 g, 68%) as a solid. mp 175-177° C.; 1H NMR (CDCl3) δ 1.91 (t, 2H, J=6.6 Hz), 2.49 (brs, 2H), 2.49-2.66 (m, 2H), 3.96-4.00 (m, 4H), 6.12 (t, 1H, J=3.9 Hz), 7.22 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=8.7 Hz), 8.05 (dd, 1H, J=2.1, 9.0 Hz), 8.36 (brs, 1H), 8.78 (d, 1H, J=2.1 Hz); ESI-MS m/z (%): 301 (M+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[N:19][N:20]=2)[N:17]=1>CN(C=O)C>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)[C:13]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: Fc1ccc(-c2nnc3cc(N4CCCC4)c(Cl)nn23)c(F)c1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccc(F)cc3F)nnc2cc1N1CCCC1
Reaction time: 18 h
Yield: 30 %

Procedure:
Sodium hydride (60% dispersion in oil, 16 mg, 0.41 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210) (38 mg, 0.33 mmol) in dry DMF (2 ml) at room temperature. After 1 h at room temperature a solution of 6-chloro-3-(2,4-difluorophenyl)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (102 mg, 0.30 mmol) was added and the reaction stirred for 18 hours. The residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (2×100 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0-2% ethyl acetate-methanol to afford the title pyridazine (42 mg, 30%). 1H NMR (250 MHz, CDCl3) 1.73-1.78 (4H, m), 3.51-3.55 (4H, m), 3.93 (3H, s), 5.40 (2H, s), 6.65 (1H, s), 6.95-7.03 (2H, m), 7.92-7.94 (1H, m), 8.04 (1H, s), MS (ES+) 413 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8](CC3C=CC(OC)=CC=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2Cc3ccc(OC)cc3C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)NC2
Temperature: 40 °C
Yield: 42 %

Procedure:
Alternatively, a mixture of 6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (98.5 mg, 0.35 mmol) in dichlormethane (10 mL) containing TFA (1.6 mL, 20.8 mmol) and TfOH (0.6 mL, 7.0 mmol) was heated overnight at 40° C. Then the mixture was poured into sodium hydrogen carbonate and water and the product extracted with dichloromethane. The combined organic layers were then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography (SiO2, dichloromethane:MeOH 20:1) to afford the title product (24 mg, 42%) as a light yellow solid. MS m/e=164.2 (M).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
A mixture of 4,4′-dibromobiphenyl (8.46 g=27.4 mmol), Pd(OAc)2 (105 mg=0.18 mmol), dppf (253 mg=0.46 mmol), N-(1-naphthyl)aniline (2.0 g=9.13 mmol) and sodium t-butoxide (1.32 g=13.7 mmol) in dry toluene was placed in a three-necked flask under a nitrogen atmosphere and stirred at 90° C. for 15 h. After cooling, the reaction was quenched by adding water and then extracted by ethyl acetate. The organic layer was dried over anhydrous MgSO4 and evaporated under vacuum. The products were purified by a silica gel column eluted with hexane. White solid of compound 2N was obtained in 70% yield (2.86 g=6.37 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([O:28][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (1.26 g, 8.92 mmol) and 3-(1-cyano-1-methylethyl)-N-(5-hydroxy-2-methylphenyl)benzamide (2.50 g, 8.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.85 g, 13.3 mmol) and the mixture was stirred at 60° C. for 4 hr, and further at 70° C. for 12 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 ml), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL) successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.41 g, 97%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.