Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:49][CH2:50][F:51])(=O)=O.O>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH2:49][CH2:50][F:51])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCCF
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CCF)CC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 80 °C

Procedure:
To a solution of 49 (70 mg, 0.111 mmol, scheme 26) in DMF (2 mL) were added K2CO3 (77 mg, 0.555 mmol) and 419 (79 mg, 0.555 mmol). The mixture was heated to 80° C. for 16 hours. Water was added to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 0-20%, (methanol/dichloromethane; SiliaFlash 10 g cartridge]. Title compound 420 was obtained as a white solid (38.9 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.68 (s, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.1, 2.0 Hz, 1H), 7.72 (dd, J=13.5, 2.4 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.22-7.17 (m, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.54 (bd, J=2.3 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.54 (s, 2H), 2.89-2.83 (m, 2H), 2.62 (t, J=5.0 Hz, 1H), 2.59-2.51 (m, 1H), 2.56 (t, J=5.1 Hz, 1H), 2.50-2.32 (m, 8H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 565.23 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=1.Cl[CH2:19][CH:20]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]3[CH:19]=[CH:20][N:17]=[C:6]3[C:5]=2[CH:4]=1
Reactant: O=CCCl
Reactant: COc1ccc2c(c1)c(N)nc1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc2c3ccccc3n3ccnc3c2c1
Temperature: 25 °C
Yield: 94 %

Procedure:
8-Methoxyphenanthridin-6-amine (0.95 g, 4.24 mmol), 2-chloroacetaldehyde (0.807 mL, 12.71 mmol), and sodium bicarbonate (1.25 g, 14.83 mmol) were added to 43 mL 2-propanol and refluxed for 15 h. After cooling to room temperature, the reaction mixture was filtered thru Celite®. After removal of the solvents, the crude material was triturated with 50 mL hexanes to give 11-methoxyimidazo[1,2-f]phenanthridine (0.99 g, 94%) as an off-white solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.CCOC(C)=O>[F:15][C:2]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cc(F)cc2c(Cl)nccc12
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(F)cc2c(F)nccc12
Temperature: 140 °C
Yield: 105.3 %

Procedure:
To a solution of 1-chloro-7-fluoro-5-methoxyisoquinoline (350 mg, 1.654 mmol) in DMSO (3 mL), was added CsF (502 mg, 3.31 mmol) and the mixture was heated to 140° C. for 4 h. The reaction was diluted with EtOAc and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give 1,7-difluoro-5-methoxyisoquinoline (340 mg, 105% yield) which was not purified further. MS m/z 196.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15](O)=[O:16])=[CH:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:9]=[C:10]([CH2:15][OH:16])[CH:11]=[CH:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(=O)n(-c2ccc(F)cc2)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1ccc(CO)cn1-c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
A 100 mL round-bottomed flask was charged with 1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1.8 g, 7.7 mmol) and 20 mL of THF. After cooling to −10° C., NEt3 (1.2 mL, 8.9 mmol) and ethyl chloroformate (0.84 mL, 8.5 mmol) were added. This mixture was stirred at that temp for 45 min, then an aq soln of NaBH4 (0.58 g, 15 mmol, in 10 mL of water) was added. After stirring for 3 h at −10° C., an additional 2 equiv of NaBH4 (solid) were added. The reaction was quenched with aq 1N HCl (50 mL) and extracted with CH2Cl2 (3×75 mL). The residue was purified by MPLC to give 1-(4-fluorophenyl)-5-(hydroxymethyl)pyridin-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=1.Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=1[O:23][CH3:24]>>[NH2:1][C:2]1[C:7]([C:8]([C:18]2[C:19]([F:21])=[CH:20][CH:15]=[C:16]([O:23][CH3:24])[C:17]=2[F:22])=[O:10])=[CH:6][N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=1
Reactant: COc1c(F)cc(F)cc1Br
Reactant: CCSc1ncc(C(=O)O)c(N)n1
Product: CCSc1ncc(C(=O)c2c(F)ccc(OC)c2F)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanylpyrimidine-5-carboxylic acid, Example 1, and 2-bromo-4,6-difluoroanisole (Astatech), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 326.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH2:27][CH2:26][CH2:25][CH2:24][C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(CCCNC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(CCCN)nc3c2C(=O)NC3)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of tert-butyl 3-(6-(2,4-dimethoxybenzyl)-5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)propylcarbamate (1.7 mg, 0.003 mmol) in TFA (2 mL) was stirred at 70° C. for 2 h. The mixture was purified by reverse phase preparative HPLC. The fractions were collected and concentrated to give a TFA salt of the title compound as a white solid (0.6 mg, 65%). 1H NMR (500 MHz, CD3OD) δ ppm 2.11-2.26 (m, 2 H), 2.30-2.45 (m, 3 H), 2.92-3.09 (m, 4 H), 4.39 (s, 2 H), 6.98 (d, J=8.34 Hz, 1 H), 7.16-7.35 (m, 1 H), 7.51 (s, 1 H), 7.65 (d, J=8.59 Hz, 1 H). [M+H] calc'd for C16H19N5O, 298; found, 298.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.Cl.[NH:40]1[CH2:43][CH:42]([OH:44])[CH2:41]1.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>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:16]([C:35]([N:40]3[CH2:43][CH:42]([OH:44])[CH2:41]3)=[O:37])[NH:17][CH:18]([CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:19]2([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])[C:20]#[N:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: OC1CNC1
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: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)N2CC(O)C2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 89 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.25 g, 0.43 mmol) was reacted with azetidin-3-ol hydrochloride (Matrix) (0.25 g, 2.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(3-hydroxy-azetidine-1-carbonyl)-pyrrolidine-3-carbonitrile as a white solid (0.2 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21

Procedure:
In the same manner as Example 1-D-02, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (40 mg) and ethanesulfonyl chloride (0.70 ml) instead of mesyl chloride, a crude product of bis-(4-methoxy-benzyl)-[5-(7-ethanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine was obtained. Using this crude product (10 mg), the PMB groups were removed according to the above Deprotection method 2, to obtain 5-(7-ethanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine as a colorless powder (4 mg, 65%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.N1C=CC=CC=1.O>C1C=CC=CC=1>[Cl:3][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nc(-c2ccccc2)cs1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: ClCc1nc(-c2ccccc2)cs1
Reaction time: 1 h

Procedure:
Thionyl chloride (6.25 g, 0.052 mole) was added dropwise to a stirred solution of 2-hydroxymethyl-4-phenylthiazole (9.55 g; 0.05 mole) and dry pyridine (4.0 g; 0.051 mole) in dry benzene (60 ml) held at room temperature. The mixture was stirred and heated to boiling for 1 hour. The cooled reaction mixture was then shaken with 2 × 70 ml H2O and dried over anhydrous MgSO4. The solvent was removed under vacuum and the remaining red oil extracted with 40°-60° C. petroleum ether (100 ml), discarding a small tarry residue. The extract was treated with decolourising charcoal, filtered and evaporated, leaving a yellow-red oil that crystallised on refrigeration.
Reaction SMILES: [C:1]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:29]([N:32]([CH3:34])[CH3:33])OC>CN(C=O)C>[CH3:29][N:32]([CH:34]=[C:23]1[CH2:24][CH2:25][N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][C:22]1=[O:26])[CH3:33]
Reactant: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A mixture of 1.94 g (5.68 mmol) of piperidinone from Step B in 10 mL of DMF was treated with 0.677 g (0.755 mL) of 1,1-dimethoxy-N,N-dimethylmethylamine. The colorless suspension was warmed to 80° C. under nitrogen. After 18 h, the mixture was cooled to ambient temperature and concentrated in vacuo. The dark red residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 2.25 g of a pale yellow-orange foam. Crystallization of a 2.03-g portion from ether (2 crops) gave a total of 1.17 g (52%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:12][CH2:13][CH2:14][CH2:15][C:16]1[O:21][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]=1>>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:22])=[O:21]
Reactant: CCCCCCCCCCN
Reactant: O=c1oc(CCCCl)nc2ccccc12
Product: CCCCCCCCCCNC(=O)c1ccccc1NC(=O)CCCCl
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
n-Decylamine (0.45 ml) was added to 2-(3-chloropropyl)-4H-3,I-benzoxazine-4-one (0.50 g). After being stirred for 45 minutes at 40° C., the reaction mixture was purified by silica gel column chromatography (silica gel 50 g, chloroform), thereby yielding 0.59 g of the aimed compound as light-yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1F)(=[O:3])[NH2:2].N=C1C=CC2[C:32](=[O:36])NC(=O)C=2C1.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:12]([NH:11][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[C:32](=[O:36])[NH:2][C:1]3=[O:3])[C:13]([OH:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: N=C1C=CC2=C(C1)C(=O)NC2=O
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2ccc3c(c2)C(=O)NC3=O)C(=O)O)cc1OC
Yield: 88 %

Procedure:
17A was prepared in a procedure similar to that of 13A using 5-iminoisoindoline-1,3-dione, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 88%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.82 (s, 3H) 3.83 (s, 3H) 5.17 (s, 1H) 6.90 (dd, J=8.35, 2.20 Hz, 1H) 6.95 (d, J=7.91 Hz, 1H) 6.99 (d, J=2.20 Hz, 1H) 7.07-7.10 (m, 1H) 7.13 (d, J=2.20 Hz, 1H) 7.50 (d, J=8.35 Hz, 1H), LCMS: 366 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.[H-].[Na+].CN(C)C=O>O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:1][C:2]2[N:17]=[CH:16][CH:15]=[CH:14][C:3]=2[C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[N:21]=1
Reactant: Nc1ncccc1C(=O)OCc1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Nc2ncccc2C(=O)OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
2.3 g (0.01 mol) of benzyl 2-aminonicotinate, 2.2 g (0.01 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.4 g (0.01 mol) of 60% sodium hydride were weighed, and 10 ml of dimethylformamide was added thereto and the mixture was stirred at 100° C. for 2 hours. The mixture was then poured into water, and was extracted with 100 ml of ethyl acetate. The extracted material was then washed with water and a saturated sodium chloride aqueous solution, and was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was recrystallized with ethanol to obtain 1.6 g of a yellow-brownish powder of the aimed product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[O:4][N:3]=1.[I:12]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[I:12][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C)no1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1onc(C)c1I
Temperature: 65 °C
Yield: 72.4 %

Procedure:
To a sealed tube fitted with magnetic stirrer was charged methyl (3-methyl-1,2-oxazol-5-yl)acetate (0.9 g, 5.8 mmol) and N-iodosuccinimide (2.61 g, 11.6 mmol) in 10 mL trifluoroacetic acid. The reaction mixture was heated at 65° C. for 3 h. The RM was quenched with NaHCO3 solution (25 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and saturated brine solution (30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown solid (1.18 g, yield: 72.4%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][NH:15][CH2:16][C:8]3=[CH:7][C:6]=2[CH:5]=1.[BH4-].[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][NH:15][CH2:16][CH:8]3[CH2:7][C:6]=2[CH:5]=1
Reactant: FC(F)(F)Oc1ccc2c(c1)cc1n2CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc2c(c1)CC1CNCCN21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 75 %

Procedure:
To 8-trifluoromethoxy-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (0.41 g) in THF (2.2 mL) and TFA (4.4 mL) at 0° C. was added portion wise sodium borohydride (0.124 g). The reaction mixture was allowed to warm up to room temperature and stirred for 35 minutes. After such time, the reaction mixture was concentrated in vacuo, and the residue was dissolved in dichloromethane and poured over water. A sodium hydroxide solution (10 M) was the added until reaching pH 13.5. After 15 minutes, the phases were separated. The aqueous phase was extracted with dichloromethane twice. The combined organic layers were then washed with brine, dried with magnesium sulfate, concentrated in vacuo and purified by column chromatography to yield the title compound (0.31 g, 76%).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:27][C:26]4[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=4)[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]-1,4-diazepan-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[C:7]([C:11](OC)=[O:12])=[CH:8][NH:9][CH:10]=1)=O.[CH3:16][NH:17][NH2:18]>>[CH3:16][N:17]1[C:11](=[O:12])[C:7]2=[CH:8][NH:9][CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:15])[CH3:1])=[N:18]1
Reactant: COC(=O)c1c[nH]cc1C(=O)CC(C)C
Reactant: CNN
Product: CC(C)Cc1nn(C)c(=O)c2c[nH]cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1H-pyrrole-3-carboxylate (Example 1, step b, 7.8 g) and methylhydrazine (6 ml) were heated at reflux for 18 hours. The solvent was evaporated and the residue was chromatographed, eluting with dichloromethane-ethanol (19:1), to give the sub-title compound as a sand coloured solid (5.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22](=O)[NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[N:40]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1.83 h
Yield: 53.2 %

Procedure:
{1-[2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (192 mg, 0.34 mmol) was dissolved in m-Xylenes (2 mL) and heated at 135° C. Solid ammonium acetate (128 mg, 1.66 mmol) was added and the reaction was stirred at 135° C. After 110 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product {1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol): LCMS-ESI+: calc'd for C22H27BrF3N5O3: 546.4 (M+). Found: 546.0/548.2 (M+H+).
Reaction SMILES: C(OC([C:6]1[S:7][C:8]([NH:11][C:12](=[O:43])[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH:39]4[CH2:41][CH2:40]4)[CH2:31][CH2:30]3)=[O:28])=[CH:15][C:14]=2[Cl:42])=[N:9][N:10]=1)=O)C.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:42][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH:39]3[CH2:40][CH2:41]3)[CH2:31][CH2:30]2)=[O:28])[C:17]([Cl:19])=[CH:18][C:13]=1[C:12]([NH:11][C:8]1[S:7][CH:6]=[N:10][N:9]=1)=[O:43]
Reactant: CCOC(=O)c1nnc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1nncs1)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 0.10 g (0.16 mmol) 5-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (Example 47) in 1 mL dioxane were added 1 mL water and 0.008 g (0.19 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred for 2 hours at room temperature and then at 80° C. for 5.5 hours. Another 0.001 g (0.024 mmol) lithiumhydroxide monohydrate was added and the reaction mixture was heated for another 1.5 hours at 80° C. After stirring at room temperature for 64 hours the reaction mixture was poured on 1M aqueous hydrochloric acid and ethyl acetate and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in N,N-dimethylformamide, filtered over a syringe microfilter and purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.030 g (33%) of the product as a light yellow solid. MS (ESI): m/z=567.08 [M+H]+.