Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:19][C:20]2[C:25](Br)=[N:24][CH:23]=[C:22]([Cl:27])[N:21]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:19][C:20]2[C:25]([O:9][CH2:3][C:4]3[O:8][CH:7]=[CH:6][CH:5]=3)=[N:24][CH:23]=[C:22]([Cl:27])[N:21]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Nc1nc(Cl)cnc1Br)c1ccc(Cl)s1
Reactant: OCc1ccco1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(Nc1nc(Cl)cnc1OCc1ccco1)c1ccc(Cl)s1
Temperature: 40 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
Sodium hydride (0.04 g of a 60% dispersion in oil) was added to furfurylalcohol (0.034 g) in 1,2-dimethoxyethane (1.0 mL). After 5 minutes 5-chloro-N-(3-bromo-6-chloro-2-pyrazinyl)-2-thiophenesulphonamide (0.1 g) was added and the mixture heated at 40° C. After 16 h, 5% aqueous citric acid (5.0 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with dichloromethane gave the title compound as a white solid (0.03 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:13](=[O:15])[CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)Cc1nc(-c2ccccc2)n[nH]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1nc(-c2ccccc2)n[nH]1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
(3-Phenyl-1H-1,2,4-triazol-5-yl)acetic acid (0.020 g) and N,N′-carbonyl diimidazole (0.016 g) in dichloromethane was stirred under nitrogen for 3 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.031 g) and triethylamine (0.036 g) was then added and allowed to stir for 1 hour under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a white solid. This was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Saturated sodium hydrogen carbonate was added to the pooled collected fractions with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetamide(0.031 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2cccc3ccc(OC(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C

Procedure:
The title product was obtained following the procedure of example 30 from 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and 4-chlorobenzoyl chloride (0.035 mL, 0.275 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) with a second equivalent of 4-chlorobenzoyl chloride added after several hours of stirring at room temperature. The title product was obtained in a yield of 0.058 g (57%) after recrystallization from ether/hexane: mp 110°-111 ° C. Analysis calculated for C22H21ClN2O2 : C, 69.38; H, 5.56; N, 7.36. Found: C, 69.31; H, 5.61; N, 7.35.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1>CN1C(=O)CCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CCO)cc1
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Yield: 32.9 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.100 g, 0.34 mmol) in NMP (3 mL) was reacted with 4-aminophenethyl alcohol (0.094 g, 0.68 mmol) to afford the title compound (0.044 g, 44%) as an off-white solid. MW=393.79. 1H NMR (DMSO-d6, 500 MHz) δ 10.20 (s, 1H), 8.30-8.25 (m, 2H), 7.78-7.56 (m, 4H), 7.29 (d, J=8.5 Hz, 2H), 7.07 (s, 1H), 4.64 (t, J=5.2 Hz, 1H), 3.66-3.60 (m, 2H), 2.74 (t, J=7.0 Hz, 2H); APCI MS m/z 394 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19]C2C=CC3C(=CC=CC=3)N=2)=[CH:14][CH:13]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:32][C:8]1([CH3:31])[NH:9][C:10](=[O:30])[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:8][CH:7]=[CH:11][CH:10]=4)[N:35]=3)=[CH:16][CH:17]=2)=[C:7]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccncc1
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: C1COCCO1
Solvent: O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) in 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1H), 8.66-8.56 (m, 2H), 8.06-7.94 (m, 2H), 7.78 (t, J=7.2 Hz, 1H), 7.66-7.56 (m, 3H), 7.30-7.18 (m, 4H), 6.98-6.88 (m, 3H), 5.36 (s, 2H), 1.36 (s, 6H). MS: M+H: m/z=422.1; M+Na: m/z=444.1. HPLC: 89%, (Condition-I).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH3:17][CH:18]([CH3:21])[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:17][CH:18]([CH3:21])[CH3:19]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: CC(C)CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(C)C)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.9 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.1 mmol 2-methyl-1-propanol and 3.3 mmol triphenylphosphine in 10 ml THF was added 3.1 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 2:3) to afford the title compound. MS (m/e): 300.2 ([M−H]−, 100%)
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][C:10]=1[C:31]([F:34])([F:33])[F:32])C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[N:25]1([C:17]2[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([C:31]([F:33])([F:32])[F:34])[CH:11]=3)[CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(N3CCOCC3)n2)ccc1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Nc1ccc(-c2cc3ncccc3c(N3CCOCC3)n2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of dibenzyl-[4-(5-morpholin-4-yl-[1,6]naphthyridin-7-yl)-2-trifluoromethyl-phenyl]-amine, 4 (29.1 mg, 0.06 mmol, 1 eq) in dry EtOH (3 mL) was added Pd(OH)2 (15 mg, 50% w/w) and 1,4-cyclohexanediene (110 μL, 1.15 mmol, 20 eq) under Ar(g). The mixture was heated at 80° C. overnight. More Pd(OH)2 (15 mg, 50% w/w) and 1,4-cyclohexanediene (110 mL, 1.15 mmol, 20 eq) were added and the mixture was again heated at 80° C. overnight. Once cooled down, the reaction mixture was filtered through a short celite pad, and eluted with MeOH (10 mL). The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (0:1) to yield the product as a pale yellow solid (10.0 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)c1
Yield: 99.8 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.058 mMol) 3-methoxybenzoyl chloride, 0.016 gm (98%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 55 °C
Yield: 83.1 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (440 mg, 0.93 mmol) in DMF (5.0 mL) was added pyrrolidine (155 μL, 1.86 mmol), triethylamine (387 μl, 2.78 mmol), and sodium iodide (1.4 mg, 0.009 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic was washed with water (2×20 mL), brine, dried (Na2SO4) and evaporated to afford 360 mg (84%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.87 (s, 1 H), 7.78 (d, 1 H), 7.56 (s, 1 H), 7.36-7.26 (m, 5 H), 7.13 (dd, 1 H), 6.57 (s, 1 H), 5.64 (s, 2 H), 2.88 (t, 2 H), 2.42-2.33 (m, 6 H), 1.78-1.66 (m, 2 H), 1.67-1.60 (m, 4 H), 1.57-1.46 (m, 2H); ES-MS m/z 466.3 [M+H]+, HPLC RT (min) 2.20.
Reaction SMILES: CO.[NH:3]1[CH:7]=[C:6]([CH:8]=O)[N:5]=[CH:4]1.[CH2:10]([NH2:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>Cl.[Pd].C(OCC)(=O)C>[CH2:10]([NH:20][CH2:8][C:6]1[N:5]=[CH:4][NH:3][CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1c[nH]cn1
Reactant: CCCCCCCCCCN
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCNCc1c[nH]cn1
Reaction time: 8 h

Procedure:
A 500 mL flask under a nitrogen atmosphere was charged with anhydrous methanol (150 mL), imidazole-4-carboxaldehyde (45.82 grams, 476 mmol) and decylamine (74.99 grams, 476 mmol) with stirring. Several drops of concentrated hydrochloric acid were added to the mixture and the mixture was allowed to reflux overnight under nitrogen. The mixture was taken up into ethyl acetate, washed with water and brine, dried with sodium sulfate, and evaporated to dryness. The crude product was dissolved in a 4:1 ratio of anhydrous THF and anhydrous MeOH and transferred to a hydrogenation reaction flask. To this solution was added 5 wt. % Pd/C (5 wt. %) and the resulting mixture was hydrogenated overnight at 30 psi H2. After hydrogenation was complete, the solution was filtered through Celite under vacuum to remove the Pd/C and the filtrate was evaporated to dryness. 1H NMR (CDCl3) δ 7.5-7.6 (1H), 6.8-6.9 (1H), 3.6-3.8 (2H), 2.6 (t, 2H), 1.5 (t, 2H), 1.2-1.4 (m, 14H), 0.8-0.9 (t, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]=2)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccccc1
Reactant: NCCCCC(=O)O
Product: ClCCCOc1ccc(C2=NCCCC2)cc1
Yield: 30.4 %

Procedure:
Following the procedure described in example 15§A, but starting from O-(3-chloropropyl)phenol (3.55 g), 5-aminopentanoic acid (2.39 g) and polyphosphoric acid (36 g) gives 1.563 g of 6-[4-(3-chloropropoxy)phenyl]-2,3,4,5-tetrahydropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([CH2:15][CH2:16][OH:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([CH2:15][CH2:16][O:17][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(O)(CCO)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(O)(CCOS(=O)(=O)c1ccc(C)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To the solution of Example 135C (8.8 g, 30 mmol) in CH2Cl2 was added tosyl chloride (2 equivalents) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 equivalents) and the mixture stirred overnight at room temperature. Purification by column chromatography on silica gel provided title compound (3.3 g, 25%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Fc1cccc(Br)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 1-bromo-3-fluorobenzene
Reaction SMILES: [F:1][C:2]1[C:18]([NH:19][C:20]2[C:23](=O)[C:22](=[O:25])[C:21]=2[O:26]C)=[CH:17][CH:16]=[C:15]([F:28])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5].[CH3:29][C:30]1[O:34][C:33]([CH:35]([NH2:41])[C:36]2([CH3:40])[CH2:39][O:38][CH2:37]2)=[CH:32][CH:31]=1>CO>[F:1][C:2]1[C:18]([NH:19][C:20]2[C:21](=[O:26])[C:22](=[O:25])[C:23]=2[NH:41][CH:35]([C:33]2[O:34][C:30]([CH3:29])=[CH:31][CH:32]=2)[C:36]2([CH3:40])[CH2:37][O:38][CH2:39]2)=[CH:17][CH:16]=[C:15]([F:28])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(Nc2c(OC)c(=O)c2=O)c1F
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(Nc2c(NC(c3ccc(C)o3)C3(C)COC3)c(=O)c2=O)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 500 mg (1.27 mmol) of methyl (S)-1-[2,6-difluoro-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]-pyrrolidine-2-carboxylate and 344 mg (1.90 mmol, 1.5 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 25 ml of methanol was heated at 60° C. and was then stirred at ambient temperature overnight. The reaction medium was concentrated. The residue was taken up with ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 0.64 g of methyl (S)-1-[2,6-difluoro-3-(2-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzoyl]pyrrolidine-2-carboxylate was obtained. Yield=93%, Mp=122° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]1[CH2:20][CH:21]=[N:22][OH:23]>CN(C=O)C.C(OCC)(=O)C>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:9])[N:11]1[CH2:20][C:21]([Cl:1])=[N:22][OH:23]
Reactant: O=C1c2ccccc2C(=O)N1CC=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Temperature: 50 °C
Yield: 98.7 %

Procedure:
N-Chlorosuccinimide (8.50 g, 63.7 mmol) was added to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanal oxime (13.0 g, 63.7 mmol) in DMF (100 mL), and the solution was heated at 50° C. gently for two hours and allowed to cool to room temperature. The solution was diluted with ethyl acetate and washed three times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated to provide 15.0 g of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[CH:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.x) (178 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (86 mg, 0.5 mmol) according to general procedure II. Obtained as a dark red solid (70 mg, 31%). MS (EI) 448.1 [(M+)]; mp 225° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]([OH:19])[CH3:18].[H-].[Na+]>>[F:12][C:8]1([C:7]2[C:2]([O:19][C@@H:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: C[C@H](O)C(F)(F)F
Reactant: N#Cc1cc(Cl)c(C2(F)CCC2)cn1
Agent: [H-]
Agent: [Na+]
Product: C[C@H](Oc1cc(C#N)ncc1C1(F)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-fluorocyclobutyl)-pyridine-2-carbonitrile (example 305c) and (S)-1,1,1-Trifluoro-propan-2-ol (CAN 3539-97-7) as starting materials and sodium hydride as reagent. The title was isolated (1.23 g, 90%) as a yellow oil; MS (ESI, m/z): 289.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17](OC)=[O:18])(=O)[CH3:14]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:13]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:17](=[O:18])[C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)[nH]c2cc(-c3ccccc3)nn2c1=O
Yield: 85.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine (4 g, 25.1 mmol) and dimethyl 2-acetylsuccinate (12 mL, 74.0 mmol) in xylene (120 mL) was added p-toluenesulfonic acid monohydrate (50 mg, 0.263 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 20 h. The solid was filtered and washed with hexanes to afford the title compound (6.4 g, 86%). 1H-NMR (400 MHz, MeOD) δ 2.37 (3 H, s), 3.66 (2 H, s), 3.72 (3 H, s), 6.46 (1 H, s), 7.34-7.53 (3 H, m), 7.87-8.06 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c21
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc(F)c3c(c2)CCC(=O)N3C)c1
Temperature: 120 °C
Yield: 49.8 %

Procedure:
A mixture of 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.066 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 27.4 mg, 0.098 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.6 mg, 0.0066 mmol) and aq. sodium carbonate solution (2 N, 0.07 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 min. The resulting reaction mixture was then diluted with EtOAc, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (12.4 mg, 50%) as a white solid. MS: 378.1 (M+H+)+.