Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:27]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-methoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (300 mg, 0.533 mmol) in DCM (5 mL) was added iodosobenzene diacetate (206 mg, 0.640 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (189 mg, 63.2% yield) as a beige solid
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:29]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCCC(CNC(=O)OC(C)(C)C)C2)n1
Yield: 83 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) with tert-butyl 3-piperidinylmethylcarbamate as in previous examples gave tert-butyl {1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methylcarbamate in 83% yield: mp (CH2Cl2/MeOH) 131-133° C.; 1H NMR (DMSO-d6) δ 7.93 and 7.89 (2d, J=8.6, 8.4 Hz, 1H), 7.68 (t, JHF=53.0 Hz, 1H), 7.46-7.38 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.91 (br, 1H), 4.54-4.41 (m, 2H), 3.97 (s, 3H), 3.79 (br s, 4H), 3.69 (br s, 4H), 3.14-3.05 (m, 1H), 2.94-2.76 (m, 2H), 1.78-1.57 (m, 3H), 1.44-1.24 (m, 2H), 1.39 and 1.32 (2s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6; H, 6.5; N, 19.5%.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18])([O-:7])=[O:6].C(Cl)(Cl)Cl>N1C(C)=CC=CC=1C>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17]([O:4][CH2:3][CH2:2][F:1])(=[O:19])=[O:18])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: OCCF
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCF)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoroethanol (1.28 g, 20 mmol) in 2,6-lutidine (20 mL) at −10° C. was added 2,4-dinitrobenzene-1-sulfonyl chloride LVI (4.91 g, 18.7 mmol) in portions. A precipitate formed so CHCl3 (50 mL) was added to the reaction mixture in order to ensure efficient stirring. After 10 min, the mixture was washed with cold 10% aqueous HCl (150 mL) and water (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1:2 EtOAc:hexane) to afford 2-fluoroethyl 2,4-dinitrobenzenesulfonate LVII (1.44 g, 4.90 mmol, 24%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 84 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-piperidin-1-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (25 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2[CH:17]=[C:18]3[N:23]([C:15]=2[CH2:14][CH2:13][NH:12]1)[CH2:22][CH2:21][CH2:20][CH2:19]3.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:12]2[CH2:13][CH2:14][C:15]3[N:23]4[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:17][C:16]=3[C:11]2=[O:24])[C:3]=1[CH:4]=[O:5]
Reactant: O=C1NCCc2c1cc1n2CCCC1
Reactant: O=Cc1c(Br)cncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Br)cncc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotinaldehyde (400 mg, 1.5 mmol), 112d (142 mg, 0.76 mmol) and cesium carbonate (176 mg, 1.5 mmol). Xantphos (40 mg, 0.08 mmol) and Pd2(dba)3 (70 mg, 0.08 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on flash column eluting with DCM:MeOH (20:1) to afford 112e (200 mg, 70%). MS: [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2.OS(O)(=O)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:28]([O-:30])=[O:29])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:22])[F:21])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCN(c1cnccc1C(F)(F)F)C2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1cnccc1C(F)(F)F)CC2
Yield: 68 %

Procedure:
6-Methyl-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (71A: 450 mg, 1.465 mmol) was reacted with concentrated H2SO4 (4.4 mL) and KNO3 (163 mg, 1.6126 mmol) for 2 hours to afford 350 mg of the product (68% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:17][CH2:18][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH2:20][CH2:21]4)[C:5]=3[C:4]1=2)(=[O:34])=[O:33]
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (1.0 g, 2.31 mmol, 1.00 equiv) in dichloromethane (20 mL) was added MsCl (632 mg, 5.54 mmol, 2.40 equiv) and triethylamine (839 mg, 8.29 mmol, 3.59 equiv) at 0° C. The resulting solution was stirred for 1 h at room temperature and quenched with water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.07 g (91%) of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate as a light yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25]([O:27]CC)=O)[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25]([NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)=[O:27])[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-2-oxo-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.27 (1H, d, J=7), 8.56 (1H, s), 8.13 (1H, s), 7.70 (1H, d, J=3.2 Hz), 7.67 (1H, d, J=3.2 Hz), 7.28-7.16 (5H, m), 5.78 (2H, s), 4.41 (1H, m), 4.09 (2H, s), 2.29 (2H, m), 2.05 (2H, m), 1.71 (2H, m); HRMS calcd for C24H22N4O3S+H+: 447.1491. Found: 447.1487.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].CS(C1C2C(=CC=CC=2)NC=1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH2:9][N:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)CCn1c(CCl)nc2cc(Cl)ccc21
Agent: CS(=O)(=O)c1c[nH]c2ccccc12
Product: CS(=O)(=O)CCn1c(Cn2nc(S(C)(=O)=O)c3ccccc32)nc2cc(Cl)ccc21

Procedure:
Example 1-12 was prepared in analogy to Example 1-2 by using 5-chloro-2-(chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]-imidazole and 3-(methylsulfonyl)-1H-indazole instead of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([C:12]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7](OCC)=[O:8].C([NH2:25])=O.CC[O-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([C:12]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7]([NH2:25])=[O:8]
Reactant: NC=O
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 5,6-dichloro-4-(3-fluorobenzylamino)nicotinate (260 mg, 0.76 mmol) in DMF (1 mL) was added HCONH2 (0.272 mL, 6.84 mmol) and NaOEt (21% in EtOH, 0.425 mL, 1.14 mmol). After stirring at room temperature for 30 min, the mixture was added water, and the precipitate was collected by filtration to give 5,6-dichloro-4-(3-fluorobenzylamino)nicotinamide (170 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[CH2:12]([O:19][CH2:20][CH:21]1[CH2:25][N:24]([C:26]2[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=2)[C:23](=[O:32])[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH2:12]([O:19][CH2:20][CH:21]1[CH2:25][N:24]([C:26]2[C:30]([N+:1]([O-:4])=[O:2])=[CH:29][N:28]([CH3:31])[N:27]=2)[C:23](=[O:32])[CH2:22]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1ccc(N2CC(COCc3ccccc3)CC2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(N2CC(COCc3ccccc3)CC2=O)n1

Procedure:
To a mixture of fuming nitric acid (0.32 mL) and acetic anhydride (5.0 mL) was added 4-((benzyloxy)methyl)-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (1.1 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, water was added thereto, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).
Reaction SMILES: [N:1]1([NH:10][C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([NH:10][C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)NN1CCc2ccccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2ccccc21
Yield: 59.5 %

Procedure:
A suspended solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (2,3-dihydro-indol-1-yl)-amide (1.00 mmol) and MnO2 (5.00 mmol) in DCM (10 mL) is stirred at rt for 60 min. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-5% methanol in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid indol-1-ylamide (196 mg, 60%) as a solid. MS: 330 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.77 (s, 3H), 6.58 (s, H), 7.15 (s, 2H), 7.26 (m, 3H), 7.84 (d, H), 8.44 (s, 2H), 8.73 (s, H), 10.94 (br, N—H). IC50=5 nM.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[CH:9]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)=[O:10].[F-].[Cs+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1.O>[F:4][C:3]([F:6])([F:5])[CH:9]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(C(O)C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
Trimethyl(trifluoromethyl)silane (3.13 mL, 21.20 mmol) was added to a mixture of ethyl 2-(3-formylphenyl)acetate (2.91 g, 15.14 mmol) and cesium fluoride (0.161 g, 1.060 mmol) in DMF (20.19 mL) cooled to 0-5° C. After stirring for 1.5 hour, a solution of TBAF 1M in THF (15.14 mL) was added. The resulting yellow solution was stirred at 0-5° C. and after 30 minutes, the mixture was poured into water (150 mL) and extracted with MTBE (1×150 mL, then 2×100 mL). The combined organic layers were washed with water (1×150 mL then 1×100 mL) and with brine (100 mL) and then the organic layer was dried over anh. MgSO4, filtered and concentrated to give 3.84 g as a light orange oil which was purified by flash chromatography to give ethyl 2-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)acetate (663 mg, 16% yield) as a colorless oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.0 Hz, 3H) 3.68 (s, 2H) 4.08 (q, J=7.0 Hz, 2H) 5.13 (q, J=7.4 Hz, 1H) 6.82 (s, 1H) 7.24-7.31 (m, 1H) 7.37 (t, J=7.2 Hz, 3H); MS m/z 263.1 (M+H)+; HPLC 93.7% @ 220 nm, RT=1.82 minutes.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1>C(C#N)(C)=O.CC(=O)OCC.O>[CH3:27][C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][N:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[O:26][CH2:25][CH2:24][O:23]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC1(CCCCBr)OCCO1
Agent: CC(=O)C#N
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(CCCCn2cc([N+](=O)[O-])cn2)OCCO1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-nitro-1H-pyrazole (2.10 g, 18.68 mmol) and Cs2CO3 (6.67 g, 20.46 mmol) in AcCN (18.9 mL) was treated with a solution of 2-(4-bromo-butyl)-2-methyl-[1,3]dioxolane (4.15 g, 18.60 mmol) in AcCN (18.9 mL). The reaction mixture was stirred at 80° C. for 2 h. Water (100 mL) was added followed by EA (100 mL). The aq. layer was extracted with EA (200 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.46. LC-MS-conditions 02: tR=0.89 min; [M+H]+=256.36. 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H), 1.38-1.53 (m, 2H), 1.65-1.77 (m, 2H), 1.90-2.02 (m, 2H), 3.88-3.94 (m, 2H), 3.94-3.99 (m, 2H), 4.17 (t, J=7.0 Hz, 2H), 8.08 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[N:38]1.C(=O)([O-])O.[Na+].O>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([C:40]3[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=3)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc2)cn1
Temperature: 95 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of (S)-3-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 mmol, 1.28 g), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.7 mmol, 0.72 g), tetrakis(triphenylphosphine)palladium(0) (0.22 mmol, 260 mg) and 2M aqueous sodium hydrogen carbonate (3.2 mL) in 1,2-dimethoxy-ethane (15 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]amino}-pyrrolidine-1-carboxylic acid tert-butyl ester 766 mg, 61%). ESI-MS m/z: 571 [M+1]+, Retention time 2.25 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[I:11]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Clc1ccc2ncc(I)n2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.4 %

Procedure:
14 g of 6-chloroimidazo[1,2-b]pyridazine (Example 1.0) were suspended in 364 ml of acetonitrile, and 20.51 g of N-iodosuccinimide were added. The mixture was stirred at RT for 19 hours. A further 4.31 g of N-iodosuccinimide were added, and the mixture was stirred for 24 hours. The reaction was cooled and the precipitated solid was filtered off with suction, washed with acetonitrile and dried. 17.67 g of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:22])[CH3:21]
Reactant: CC(C)c1ccccc1N
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: Cc1ccc2c(c1)C(C(=O)Nc1ccccc1C(C)C)c1ccccc1CO2
Yield: 126 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of Compound A and 0.63 g of 2-isopropylaniline in place of aniline to obtain 1.84 g of Compound 5.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]1([P:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:20]CC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)C>C(N(CC)CC)C>[C:13]1([P:19]([C:4](=[O:5])[C:3]2[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=2[CH3:12])(=[O:20])[O:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOP(Oc1ccc(OC)cc1)c1ccccc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: CCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OP(=O)(C(=O)c2c(C)cc(C)cc2C)c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
59.5 g (0.326 mol) of 2,4,6-trimethylbenzoyl chloride and 0.75 g of triethylamine were heated to 115° C. and 45 g (0.163 mol) of monoethyl mono-4-methoxyphenyl phenylphosphonite were added dropwise in one hour under a nitrogen atmosphere and with vigorous stirring. Ethyl chloride was given off as a gas and was condensed in a downstream cold trap. The mixture was then further stirred at 110° to 115° C. for 90 minutes. In total, at the end of the reaction, 9 g (88% of theory) of ethyl chloride were situated in the cold trap. The excess 2,4,6-trimethylbenzoyl chloride was then distilled off at 1 mbar and the residue was distilled with the aid of a thin-film evaporator (bath temperature: 260° C.; 0.4 mbar). 40 g were obtained. The yield was 65% of theory.