Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14](O)=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:17]=1.C(Cl)(=O)C(Cl)=O.C[N:25](C=O)C>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([NH2:25])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:17]=1
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCc2sc3ccc(F)cc3c2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1CCc2sc3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of 8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylic acid (1.2 g, 4.8 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.55 mL, 6.24 mmol) and a drop of DMF. The reaction was stirred at room temperature for 30 min, then was concentrated in vacuo. The resulting residue was dissolved in acetone (30 mL) and cooled to −5° C. Conc. NH4OH (10 mL) was added quickly, resulting in a white precipitate. The suspension was stirred for 30 min, then diluted with water and filtered to afford 1.14 g (95%) of the title compound as a white solid: mp 201-202° C.; MS (−) 248 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:21]O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[N:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cc(Cl)cc(Cl)c1
Agent: Cl[Fe]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: FC(F)(F)c1ccc2cc(-c3cc(Cl)cc(Cl)c3)nn2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.4 %

Procedure:
To a suspension of 1-(3,5-dichlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (13.30 g, 38 mmol) in DME (52 ml) at 5° C. was added TFAA (6.25 ml, 44 mmol) and the mixture stirred for 10 minutes. Triethylamine (18.6 ml, 134 mmol) was then added dropwise over 15 min. After the addition was complete, the reaction mixture was then warmed to room temperature. After stirring for 1 hour, iron (II) chloride (56 mg) was added and the mixture was then heated to 75° C. for 1 hour then allowed to cool. The mixture was poured into water (500 ml) and extracted with dichloromethane (300 ml). The organic extracts were dried over MgSO4 and concentrated under reduced pressure to ca. 50 ml. This residue was purified by filtration through a layer of silica gel washing with further dichloromethane. The filtrate was concentrated to dryness to give 3.2 g (25%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(N)=[O:23].O.CCOC(C)=O>O1CCOCC1>[OH:23][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CO)c1c[nH]c2cc(OCc3ccccc3)ccc12
Temperature: 110 °C
Reaction time: 10 h
Yield: 82 %

Procedure:
A solution of 11 in dioxane was added to formamide-water (10:1). The mixture was stirred at 110° C. for 10 hrs., then worked up and purified as described above to yield 82% of 13 as colorless prisms with mp 194°-195° C. (EtOAc).
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][C:18]1[CH:37]=[CH:36][C:21]2/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[O:25][CH2:26][C:20]=2[CH:19]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:23]2=[C:24]([CH:27]=1)[O:25][CH2:26][C:20]1[CH:19]=[C:18]([CH2:17][N:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[N:8]=[C:7]3[N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:37]=[CH:36][C:21]=1/[C:22]/2=[C:32](/[CH3:35])\[C:33]#[N:34]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1ccc2[nH]c(N3CCCCC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(N4CCCCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 76.8 %

Procedure:
Using commercially available 2-(piperidin-1-yl)-1H-benzo[d]imidazole (67 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.34 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (125 mg, 78%) was obtained.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[C:18]([O:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH:17]=2)=[O:15])[CH3:12])=[O:10])[CH2:5][CH2:4]1)#[N:2].N1C=CC=CC=1.C(N(CC)CC)C.[SH2:53]>C(OCC)(=O)C>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([O:31][CH2:32][C:33]([OH:35])=[O:34])[CH:17]=2)=[O:15])[CH3:12])=[O:10])[CH2:5][CH2:4]1)(=[S:53])[NH2:2]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)[C@H]1CC[C@H](C#N)CC1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(N)=S)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into the solution of the compound prepared in (a) (655 mg, 1.2 mmole) in the mixture of pyridine (15 ml) and triethylamine (1 ml) was streamed a hydrogen sulfide gas for 1 hour, and the mixture was stirred in a sealed tube at 50° C. for 5 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate, and washed twice with each of a 5% aqueous sodium hydrogen carbonate and a 1M potassium hydrogen sulfate solution. After the organic layer was dried over anhydrous magnesium sulfate, the inorganic salt was removed by filtration. The filtrate was concentrated under reduced pressure, and the oily product thus obtained was purified by column chromatography on silica gel with an eluent system of chloroform:methanol =50:1 to give 71 mg of the thioamide derivative as a yellow oily product (yield, 10%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)[N:3]=[CH:4][N:5]=1
Reactant: N#Cc1c(Cl)ncnc1Cl
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(Nc2ncnc(Cl)c2C#N)cc1

Procedure:
Intermediate 4-chloro-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile was prepared in a similar manner as described herein using 4,6-dichloro-pyrimidine-5-carbonitrile and 4-methylsulfanyl-phenylamine. 1H-NMR (DMSO-d6): 10.22 (1H, s), 8.53 (1H, s) 7.43 (2H, m), 7.40 (2H, m), 2.49 (3H, s) ppm. LCMS: 277.0, 234.0, 149.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:18])C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2ccccc2)cc1
Product: O=c1cc(OCc2ccccc2)cc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
4-Benzyloxypyridine 1-oxide (24.8 g, 123 mmols) was refluxed in acetic anhydride (150 mL) for 1.5 hours. Cooling the system to room temperature, the system was concentrated under reduced pressure and the resulting residue was dissolved in a mixed solvent of ethyl acetate (150 mL) and methanol (10 mL), followed by stirring at 60° C. for 2 hours. The solid formed upon cooling the system to room temperature was recovered by filtration to provide crude title compound (8.84 g). Concentrating the filtrate, additional crude title compound (4.17 g) was obtained. The combined crude product was recrystallized from a mixed solvent of methanol and ethyl acetate to provide the title compound (12.1 g, 49%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([Sn](C)(C)C)=[N+:28]=[N-:29]>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:26])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[NH:29][N:28]=[N:27][N:25]=3)[CH:19]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)C(=O)N1CCC(Cc2ccccc2)CC1
Yield: 53.8 %

Procedure:
A mixture of 0.7 g (2 mmol) of 2-(4-benzyl-piperidin-1-yl)-N-(3-cyanophenyl)-2-oxo-acetamide, 0.82 g (4 mmol) of azidotrimethyltin (Aldrich) and 20 ml of toluene is refluxed for 20 hours. The precipitated crystals are filtered off and treated with 20 ml of N hydrochloric acid to yield 0.42 g (54%) of the title compound. Melting Point: 159-161° C. (water)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)[C:19]=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]CCOS(C)(=O)=O)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:19][CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 76.9 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 76.9%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].[ClH:19]>[Pd].C(O)(=O)C>[ClH:19].[NH2:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1OS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)cc1OS(C)(=O)=O

Procedure:
Methyl 2-methanesulfonyloxy-4-nitrobenzoate (14 g) and palladium on carbon (0.5 g, 10%) were suspended in 400 ml of acetic acid and hydrochloric acid (5 ml, density 1.18). The suspension was hydrogenated in a Parr hydrogenation apparatus at 250 kPa. The palladium carbon was filtered off, and the solution was evaporated; the crystal mass was washed with ethyl acetate and dried. Yield: 11 g.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:20]=3[NH:19][C:18]3[C:13]4=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].C([O-])([O-])=O.[K+].[K+]>C(OCCCC)CCC.[Cu].[Cu]I>[CH:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:6]=1[NH:7][C:8]1[C:9]2=[CH:10][CH:11]=[C:12]2[C:20]=1[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28])[C:18]1[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1ccccc1I
Reactant: c1ccc2c(c1)[nH]c1c2ccc2c3ccccc3[nH]c21
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCCCOCCCC
Product: Sc1ccccc1-n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Temperature: 144 °C
Reaction time: 96 h

Procedure:
25 g (96.6 mmol) of 11,12-dihydroindolo[2,3-a]carbazole are added to 12.5 g (48 mmol) of 2-iodobenzenethiol in 80 ml of di-n-butyl ether, and the solution is degassed. 6.6 g (0.105 mmol) of copper powder, 0.92 g (0.003 mmol) of copper(I) iodide and 14.6 g (106.6 mmol) of K2CO3 are subsequently added to the mixture, which is then stirred at 144° C. under protective gas for 4 days. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 22.5 g (61 mmol), 66% of theory, purity according to HPLC 89.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2.C([O-])(O)=O.[Na+].[I:26]Cl>C(Cl)Cl.CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:26])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:5]2
Reactant: ClI
Reactant: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (560 mg, 2.09 mmol) in a mixture of CH2Cl2 (10 mL) and MeOH (2.5 mL), was added NaHCO3 (263 mg, 3.13 mmol) followed by 1M ICl in CH2Cl2 (2.1 mL, 2.1 mmol). The mixture was stirred for 30 min and then quenched with sat. aq. NaHSO3. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-amino-6-iodo-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=395.0; found=394.7 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.58-7.51 (2 s, 1H); 7.45-7.35 (m, 5H); 6.70-6.64 (2 s, 1H); 5.24 (s, 2H); 4.67 (s, 2H); 4.65 (s, 2H); 4.15 (br, s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:19])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[O:6][CH:7]=1.[CH2:20]=[O:21].[OH-].[Na+]>O1CCOCC1>[OH:1][C:2]1[C:3](=[O:19])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[O:6][C:7]=1[CH2:20][OH:21]
Reactant: C=O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.5 %

Procedure:
To a stirred solution of N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (8-01) (1.1 g, 3.92 mmol) in dioxane (20 mL) were added 37% formaldehyde solution (0.47 mL, 4.69 mmol) and aqueous NaOH (1.95 mL, 3.92 mmol, 2M) and the mixture was stirred for 6 h at room temperature. After completion of the reaction, it was concentrated under vacuum to get a crude compound. It was then purified using normal column chromatography to get N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (9-01) (470.0 mg, 38.57%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:13].O=S(Cl)Cl.[CH3:18][CH2:19]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:18][CH3:19])=[O:10])=[CH:4][C:3]=1[F:13]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(N)c(F)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)c1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 2-(4-Amino-3-fluorophenyl)propionic acid (1 g, 5.459 mmol) in EtOH was added SOCl2 (0.6 ml, 8.189 mmol) at 0° C. The mixture was stirred for 2 hours at room temperature and then SOCl2 was removed under reduced pressure. The residue was diluted with EtOAc and washed with a saturated NaHCO3 solution. The resulting mixture was dried over MgSO4 and concentrated. The residue was purified by column chromatography to afford ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 87%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:7]2[N:8]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:39]=[N+:40]=[N-:41])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:41][N:40]=[N:39][N:34]=3)=[CH:25][CH:26]=2)[C:7]2[N:8]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2c(-c3ccccc3)c(C)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nn2c(-c3ccccc3)c(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 32 %

Procedure:
Following the procedure of Example 1, Step G, 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-methyl-6-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step B) was reacted with trimethyltin azide to give a 32% yield of the title compound as a brown solid, mp>108° C. (gradual); homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C(Cl)(Cl)Cl.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>O>[Cl:12][C:3]1[C:2]([NH:1][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][CH:6]=[C:5]([C:8]([F:9])([F:11])[F:10])[N:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To a mixture of 3-amino-2-chloro-6-trifluoromethylpyridine (3.93 g) and chloroform (30 ml), pivaloyl chloride (2.65 g) and triethylamine (4.04 g) were added under ice-cooling, and stirred at room temperature for 2 hours, then at 60° C. for 2 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 6.59 g of N-(2-chloro-6-trifluoromethylpyridin-3-yl)-2,2-dimethylpropionamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([C:9]1([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:11][CH2:12][C:8]1=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1(Cc2ccccc2)CCCC1=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
29.0 grams of anhydrous potassium carbonate and 132 ml of acetone were mixed, then with stirring, to the resulting mixture was dropwise added a solution of 13.0 ml of methyl 2-oxocyclopentane carboxylate in 66 ml of acetone. After stirring at room temperature for 30 minutes, 13.7 ml of benzyl bromide was dropwise added thereto, and the reaction was allowed to continue under reflux for 6 hours. Then the reaction mixture was cooled to room temperature, filtered, and concentrated, and 150 ml of toluene was added thereto. The resulting solution was washed with water (3×150 ml), dried over anhydrous sodium sulfate, concentrated, and distilled under reduced pressure. 13.4 g of colorless liquid as a distillate cut of 161-162° C./4.8 mmHg was collected. Yield: 55.1%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:10]3=[CH:9][C:8]=2[CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>>[N:21]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]3[N:11]4[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:10]4=[CH:9][C:8]=3[CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=C1NCCCn2c1cc1cc(OCCCCl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCCn2c1cc1cc(OCCCN3CCCC3)ccc12
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 2, from 9-(3-chloro-propoxy)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, pyrrolidine (commercially available) and potassium carbonate, to give the desired product as a light yellow solid (50%).
Reaction SMILES: [CH2:1]([N:3]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:4]1[C:5]([CH3:19])=[C:6]([CH:11]=[C:12]([CH:14]2[CH2:17][N:16]([CH3:18])[CH2:15]2)[CH:13]=1)[C:7](OC)=[O:8])[CH3:2].[OH-].[Na+].Cl.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.[NH2:62][CH2:63][C:64]1[C:65](=[O:72])[NH:66][C:67]([CH3:71])=[CH:68][C:69]=1[CH3:70]>C1COCC1.CN(C=O)C.CO>[CH3:70][C:69]1[CH:68]=[C:67]([CH3:71])[NH:66][C:65](=[O:72])[C:64]=1[CH2:63][NH:62][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([CH:14]2[CH2:15][N:16]([CH3:18])[CH2:17]2)[CH:13]=[C:4]([N:3]([CH2:1][CH3:2])[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]=1[CH3:19]
Reactant: CCN(c1cc(C2CN(C)C2)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
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: CN(C)C=O
Solvent: CO
Product: CCN(c1cc(C2CN(C)C2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
Methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-(1-methylazetidin-3-yl)benzoate (103 mg, 0.30 mmol) was dissolved in THF (20 ml) and MeOH (5 ml) and 2M NaOH (1.49 ml, 2.97 mmol) was added. The reaction was stirred at 50° C. for 16 h, cooled, acidified to pH4 using 6M HCl and the solvent evaporated under reduced pressure, and the residue dried in a vacuum oven at 40° C. for 5 h to afford the crude acid. To the acid in DMF (10 ml) were added HATU (170 mg, 0.45 mmol) and DIPEA (130 μl, 0.74 mmol). The mixture was stirred at room temperature for 5 min and then 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 66 mg, 0.39 mmol) was added. The reaction was stirred for 16 h after which additional HATU (80 mg) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (30 mg) and the mixture stirred a further 5 h. The reaction mixture was poured onto distilled after (50 ml), extracted with EtOAc (3×50 ml), washed with brine (2×20 ml), dried with Na2SO4, filtered and evaporated. The crude residue was purified using preparative HPLC and evaporated to afford the title compound as an off-white solid (28 mg, 5% over three steps). LC-MS 95%, m/z=467.3, 1H NMR (500 MHz, Acetone-d6) δ 10.73 (s, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 5.97 (s, 1H), 4.74 (t, J=9.9 Hz, 2H), 4.60 (t, J=9.6 Hz, 2H), 4.38 (q, J=6.2 Hz, 3H), 3.83 (d, J=11.6 Hz, 2H), 3.27 (s, 3H), 3.23 (t, J=11.6 Hz, 2H), 3.10 (dd, J=14.1, 7.0 Hz, 2H), 3.04-2.97 (m, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.67 (d, J=11.1 Hz, 2H), 1.56 (td, J=11.8, 4.1 Hz, 2H), 0.83 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:28])[C:25]([NH2:27])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:28])[C:25]([NH2:27])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C(C)C(N)=O)n2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C(C)C(N)=O)n2)cn1
Yield: 63 %

Procedure:
A solution of 2-(2-((2-((6-methoxypyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)propanamide A69 (0.198 g, 0.449 mmol) in EtOAc (20 mL) and MeOH (10 mL) was stirred over 10% Pd/C (wetted with ca. 53% water, 0.150 g) under an atmosphere of hydrogen for 16 hours. The mixture was filtered through Celite and the solvent was removed in vacuo. Purification by column chromatography (Biotage Isolera, 40 g SiO2, 0-80% EtOAc in petroleum benzine 40-60° C.) gave the title compound 61 as a white solid (0.126 g, 63%). LCMS-D: rt 3.43 min; m/z 446 [M+H]+.