Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14](F)[CH:13]=1)[CH:2]=[CH2:3].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NCc2ccc(OC)cc2)c1

Procedure:
Analogously to Example 33, 17.55 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-(4-bromo-phenyl)-methanone are boiled under reflux for 23 hrs. with 50.7 ml of 4-methoxybenzylamine and 6.5 g of potassium carbonate in 600 ml of toluene. After filtration, evaporation and purification over silica gel with methylene chloride/methanol (2.5% to 10%) there are obtained 17.43 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-(4-methoxy-benzylamino)-phenyl]-(4-bromo-phenyl)-methanone. A solution of this material in 200 ml of trifluoroacetic acid is stirred at room temperature for 45 hrs., evaporated and the residue is converted into the free base with methylene chloride/saturated sodium bicarbonate solution. After purification over silica gel with methylene chloride/methanol (9:1) there are obtained 13.23 g of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone. 9.1 g of the free base are dissolved in methylene chloride/ether and converted with 2.25 g of fumaric acid and by stirring overnight into 7.28 g of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone•fumarate (1:1), m.p. 78° C. (with decomposition).
Reaction SMILES: [NH2:1]CC(O)=O.[CH2:6]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)[CH3:7].N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH3:19][O:18][C:16](=[O:17])[CH2:15][N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:6][CH3:7])[CH:9]=1)[NH2:1]
Reactant: CCc1cccc(NCC(=O)OC)c1
Reactant: NCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cccc(N(N)CC(=O)OC)c1
Reaction time: 2 h
Yield: 14 %

Procedure:
To the glycine (Intermediate 38; 35 g; 0.181 mol) in acetic acid (50 ml) at -5° C. was added, dropwise, a solution of sodium nitrite (13.75 g; 0.199 mol) in H2O (10 ml). The temperature of the reaction mixture was not allowed to rise above 0°. After stirring for a further 2 h, zinc dust (26.02 g, 0.398 mol) was added portionwise, once again so as not to allow the temperature of the reaction mixture to rise above 0°. After 5 h, a further quantity of zinc dust (13.01 g, 0.199 mol) was added and the mixture was stirred overnight. The excess zinc dust was removed by filtration through celite. The reaction mixture was then quenched with sodium bicarbonate solution. Extraction into ethyl acetate followed by washing with water, brine and finally drying (over Na2SO4) gave the crude title compound (ca. 35 g). This crude material was chromatographed using Ethyl acetate: Petroleum ether (1:3) to yield Intermediate 39 (5.21 g; 14%) as an oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@H:72]5[CH2:76][CH2:75][O:74][CH2:73]5)=[C:64]([F:77])[CH:63]=4)=[C:53](C)[CH:52]=3)[C:48]([OH:50])=O)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:44](=[CH:43][C:42]([NH:46][CH:47]3[C:48](=[O:50])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@H:72]4[CH2:76][CH2:75][O:74][CH2:73]4)[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:11])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:41][CH:40]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:85])([CH3:87])[CH3:86])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@H]1CCOC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@H]3CCOC3)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To BOP (317 mg, 0.716 mmol), 4-dimethylaminopyridine (219 mg, 1.791 mmol) in CH2Cl2 (40 mL), was added a solution of 39E (298 mg, 0.358 mmol) in DMF (10 mL) via a syringe pump over 6 h. The mixture was stirred rt for 16 h, then concentrated and purified by prep HPLC to give 39F (180 mg, 61.7% yield). MS (ESI) m/z: 814.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([CH3:14])=[CH:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.[CH:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O.[C:27]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])#[N:28].N1CCCCC1>C(O)C>[C:12]([C:11]1[CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:27](=[NH:28])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=2)[C:10]=1[CH3:14])#[N:13]
Reactant: CN(C)C(=O)CC#N
Reactant: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)C(C(=O)N(C)C)C(=N)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Under argon, 100 mg (0.44 mmol) of the compound of Example 2A, 57.97 mg (0.44 mmol) 4-formylbenzonitrile and 49.57 mg (0.44 mmol) 2-cyano-N,N-dimethylacetamide are dissolved in 2 ml ethanol. 3.76 mg (4.4 μl, 0.04 mmol) piperidine are added, and the mixture is stirred at reflux overnight. After cooling down to room temperature, the crude product is purified by column chromatography with cyclohexane/ethyl acetate 20:1, 10:1, 8:1, 6:1, 4:1, 2:1, 1:1, 1:2 and dichloromethane/methanol 100:1, 50:1, 20:1 as eluents. The product containing fractions are repurified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>O1CCCC1>[Br:1][C:2]1[C:3]([CH:20]=[O:21])=[C:4]([Cl:8])[N:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(Br)ccn1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Br)ccnc1Cl
Temperature: -70 °C
Yield: 30.2 %

Procedure:
To a solution of 4-bromo-2-chloropyridine (12.0 g, 60.0 mmol) in anhydrous tetrahydrofuran (300 mL) cooled at −70° C. was added the solution of lithium diisopropylamide (30.0 mL, 60.0 mmol, 2.0 M) over a period of 30 minutes and stirred for another at −70° C. 2 h. Anhydrous DMF (12.0 g) was introduced over a period of 10 minutes and stirred for another 30 minutes. It was then quenched with saturated NaHCO3 (200 mL), extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (20:1) to afford 104a as a yellow solid (4.0 g, 29%). 1H NMR (500 MHz, DMSO) δ 10.23 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 7.94 (d, J=5.5 Hz, 1H).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][CH2:13][C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[Cl:12][CH2:13][C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:31])([F:32])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])=[O:15]
Reactant: O=C(CCl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(CCl)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 89 %

Procedure:
1.03 ml (0.011 mol) of acetic anhydride and 0.56 ml (0.013 mol) of 98 percent strength nitric acid are added successively to 4.2 g (0.011 mol) of 5-chloroacetamido-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of glacial acetic acid at 15° C. After stirring for 6 hours, the mixture is concentrated in vacuo, the residue is taken up in 100 ml of dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed of solvent in vacuo. 4.1 g (89% of theory) of 5-chloroacetamido-4-nitro-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 130° C.-133° C. are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]C=1C=O.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[NH:1]1[C:3]2=[N+:4]([O-:21])[CH:5]=[CH:6][CH:7]=[C:8]2[CH:9]=[CH:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cnc2ccccc2n1
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Yield: 67.6 %

Procedure:
A solution of 7-azaindole 22-1 (30.6 g, 259 mmol) in methylene chloride (300 mL) was treated with mCPBA (75.6 g, 285 mmol) at room temperature for 12 h. The reaction mixture was washed with saturated aqueous NaHCO3 (3×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel chromatography (100×250 mm silica, 10% to 50% EtOAc/hexanes) afforded 23.5 g of 1H-pyrrolo[2,3-b]pyridine 7-oxide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@@H:15](O)[CH2:14][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[F:47][C:48]1([F:54])[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]([N:50]3[CH2:51][CH2:52][CH2:53][C:48]([F:54])([F:47])[CH2:49]3)[CH2:14][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: FC1(F)CCCNC1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)c1cccc(C#N)c1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](N2CCCC(F)(F)C2)CN1S(=O)(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the compound of Step 1 (19.6 g, 63.2 mmol), diisopropylethylamine (16.5 g, 127 mmol), and CH2Cl2 (200 mL) was added trifluoromethanesulfonic anhydride (17.8 g, 63.2 mmol) via syringe pump at −60° C. over 30 minutes. The resulting solution was then warmed to −20° C. over 1.5 h, whereupon diisopropylethylamine (5.5 g, 42.5 mmol) was added followed by 3,3-difluoropiperidine hydrochloride (6.67 g, 42.5 mmol). The mixture was then slowly warmed to rt over 5 h. After 12 h at rt, the reaction was partitioned between H2O (150 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→99:1 ethyl acetate-hexanes) to afford the title compound as a colorless foam: 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.68 (t, 1H), 4.48-4.59 (m, 1H), 3.73 (s, 3H), 3.68-3.65 (m, 1H), 3.22-3.17 (m, 2H), 2.64 (br q, 1H), 2.51 (br q, 1H), 2.42-2.41 (m, 2H), 2.23-2.20 (m, 1H), 2.13-2.04 (m, 1H), 1.90-1.82 (m, 2H), 1.74-1.72 (m, 2H); LRMS (ESI) m/z 414 (414 calcd for C18H21F2N3O4S, M+H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:20]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C2CCCCCC2)cc1

Procedure:
In analogy to the procedure of Example I, the title compound is prepared from 31.7 g (0.293 mol) of anisole, 47 g (0.352 mol) of aluminium chloride and 49.5 g (0.308 mol) of cycloheptanecarbonyl chloride.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:22][C:23]1[C:29]([CH:30]([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].[OH-].[K+]>O.CCOCC.C(O)CC>[CH3:22][C:23]1[C:29]([CH:30]([F:31])[F:32])=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(N)cccc1C(F)F
Reactant: O=C(O)c1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Solvent: CCOCC
Solvent: O
Product: Cc1c(Nc2ncccc2C(=O)O)cccc1C(F)F

Procedure:
With stirring, reflux a mixture containing 5 g. of 2-chloronicotinic acid, 0.3 g. of p-toluene sulfonic acid, 12.5 g. of 2-methyl-3-difluoromethyl aniline, and 15 ml. of n-propanol for five hours. Treat the reaction mixture with ether and 6.2 g. of potassium hydroxide dissolved in 100 ml. of water. Separate and acidify the aqueous layer with dilute hydrochloric acid to yield the product 2-(2-methyl-3-difluoromethylanilino) nicotinic acid, m.p. 232°-234° after recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl.[NH2:5][C:6]1([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19]O>>[O:18]=[C:15]1[NH:16][CH:17]=[C:12]([C:6]2([NH:5][C:1](=[O:2])[CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH:13]=[CH:14]1
Reactant: NC1(c2ccc(=O)[nH]c2)CCCCC1
Reactant: CO
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)NC1(c2ccc(=O)[nH]c2)CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium methoxide solution (25% in methanol, 6 ml) was added to a suspension of 5-(1-aminocyclohexyl)-2(1H)-pyridinone hydrochloride (6.0 g) in 100 ml of methanol, and the mixture was stirred at room temperature for 10 minutes. The solvent was removed in vacuo, and the residual solids were suspended in 260 ml of dichloromethane. Poly-4-vinylpyridine (5.42 g), acetic anhydride (2.67 g) and a catalytic amount of 4-(N,N-dimethylamino)pyridine were added, and the mixture was stirred at room temperature for 2 hours. The suspension was filtered and the solid residue was washed with methanol. The filtrate was concentrated, leaving 4.9 g of solid. Recrystallization from methanol gave 1.69 g of product (m.p. 238°-242° C. dec) in two crops, each of which was analytically pure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[N:7][CH:8]=1.[H-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:12][CH2:13][CH2:14][CH2:15][O:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[N:7][CH:6]=1
Reactant: COc1cncc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cncc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-methoxypyridin-3-ol (0.50 g, 4.01 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.19 g of an 80% dispersion in mineral oil, 6.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (0.98 g, 4.81 mmol), and the resulting dark brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (0.75 g, 92.8%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.[C:22](O)(=[O:26])[C:23]#[C:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:22](=[O:26])[C:23]#[C:24][CH3:25])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Reactant: CC#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CC(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one hydrochloride 103a (1.0 g, 2.66 mmol), but-2-ynoic acid (268 mg, 3.19 mmol), HATU (1.21 g, 3.19 mmol) and DIPEA (1.14 mL, 6.65 mmol) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was diluted with EA and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was washed with PE/EA (2 mL/20 mL) and dried to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)but-2-ynamide 116a (800 mg, 74%) as light yellow solid. ESI-LCMS: m/z=404.9
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([OH:20])([C:23]([F:25])([F:24])[F:22])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)c2c1OCO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid and 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4 hours to 70° C. Then, the batch is concentrated by evaporation in a vacuum and added to water. It is extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 272 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a yellow oil. This ester and 0.32 ml of trifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml of a tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It is stirred for 1 hour at 70° C, for 1.5 hours at −10° C., for 1 hour at 0° C. and for 2 hours at room temperature. Another spatula-tip full of tetrabutylammonium fluoride is added, and after stirring is continued for 20 minutes, it is added to water. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 297 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 ml of ether at 0° C. with 29 mg of lithium aluminum hydride, and stirred for 1 hour at 0° C. and for another 10 hours at room temperature. The batch is added to dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 164 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is obtained as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[CH2:27](Br)[C:28]#[CH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]=[C:2]1[N:8]([CH2:29][C:28]#[CH:27])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (160 mg, 0.451 mmol) in DMF (2 mL) was added propargyl bromide (80 mg, 0.672 mmol) and powdered cesium carbonate (219 mg, 0.672 mmol). The mixture was stirred under nitrogen at ambient temperature for 18 h. The reaction was diluted with water and extracted twice with ethyl acetate. The residue obtained from the combined organic extracts was purified by flash chromatography on silica gel eluting with 5:1 (v/v) hexane:ethyl acetate to afford the title compound (143 mg, 80%) as a white solid. TLC Rf=0.19 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.38 (s, 9H), 2.30 (m, 1H), 4.69 (m, 2H), 4.96 (m, 2H), 5.66 (m, 1H), 7.28 (m, 3H), 7.39 (s, 5H), 7.48 (m, 1H). MS APCI, m/z=293 (M+1). LC/MS: 2.86 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=O)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=C.C(N1CCOCC1)C>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[C:7]([CH:8]=[CH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C=Cc1c(F)c(F)c(F)c(F)c1F

Procedure:
0.0561 g (0.25 millimol) of palladium acetate, 5.76 g (25 millimols) of pentafluorobenzoyl chloride, 2.50 g (25 millimols) of ethyl acrylate and 2.88 g (25 millimols) of N-ethylmorpholine, in 100 ml of xylene, are stirred for 6.5 hours at 130° C. The crude product is distilled in vacuo. 3.9 g (59% of theory) of a colourless liquid (which distils at 61°-64° C./12 Pa) are obtained. Analysis for C11H7F5O2 : calculated C 49.64%, H 2.65%, F 35.69%; found C 49.76%, H 2.72%, F 35.90%.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH2:22][C:23](Cl)=[N:24][OH:25])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 94-1-3 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=1:3→1:2) to obtain the title compound (18.0 mg, 13.5%).