Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([CH:23](OS(C)(=O)=O)[C@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]4)=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1>[Pd].C1COCC1>[F:39][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]4)=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(OS(C)(=O)=O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A mixture of methyl trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl][(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate (100 mg, 0.18 mmol) and palladium on carbon (10 mg, 10 wt %) in THF (10 mL) was stirred under a hydrogen atmosphere (45 psi) at 40° C. for 48 hours. The reaction mixture was then filtrated and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give methyl trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylate. MS ESI calc'd for C25H28F2N5O2[M+H]+ 468. found 468. 1H NMR: (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.65 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.22 (s, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.60 (t, J=54.4 Hz, 1H), 3.66 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.45 (s, 3H), 2.33-2.30 (m, 1H), 2.01-1.97 (m, 3H), 1.81-1.79 (m, 2H), 1.48-1.41 (m, 2H), 1.19-1.17 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:26]2[S:30][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12]([C:26]3[S:30][C:29]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2ccc(CN3CCCCC3)s2)OC1(C)C
Product: Nc1ncc(-c2ccc(CN3CCCCC3)s2)nc1C(=O)Nc1ccncc1

Procedure:
The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide (synthesis described for “A10”) with 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-piperidine gives the compound “A13”;
Reaction SMILES: ClC1C2C=C(C(NC3C=CC(N4CCN(C(=O)CC(C)(C)C(O)=O)CC4)=NC=3)=O)SC=2C=CC=1.[CH2:35]([N:37]1[C:45]2[C:40](=[C:41]([CH3:46])[CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]2[CH2:61][CH2:60][N:59]([C:62](=[O:70])[CH2:63][C:64]([CH3:69])([CH3:68])[C:65]([OH:67])=[O:66])[CH2:58][CH2:57]2)=[CH:52][CH:51]=1)=[O:48])[CH3:36].N1CCC(C2C=CC(NC(C3N(CC)C4C(C=3)=C(C)C=CC=4)=O)=CC=2)CC1.CC1(C)CC(=O)OC1=O>>[CH2:35]([N:37]1[C:45]2[C:40]([CH:41]([CH3:46])[CH:42]=[CH:43][CH:44]=2)=[CH:39][CH:38]1[C:47]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([CH:56]2[CH2:57][CH2:58][N:59]([C:62](=[O:70])[CH2:63][C:64]([CH3:68])([CH3:69])[C:65]([OH:67])=[O:66])[CH2:60][CH2:61]2)=[CH:54][CH:55]=1)=[O:48])[CH3:36]
Reactant: CCn1c(C(=O)Nc2ccc(C3CCN(C(=O)CC(C)(C)C(=O)O)CC3)cc2)cc2c(C)cccc21
Agent: CC(C)(CC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1)C(=O)O
Agent: CC1(C)CC(=O)OC1=O
Agent: CCn1c(C(=O)Nc2ccc(C3CCNCC3)cc2)cc2c(C)cccc21
Product: CCN1C2=CC=CC(C)C2=CC1C(=O)Nc1ccc(C2CCN(C(=O)CC(C)(C)C(=O)O)CC2)cc1

Procedure:
With a method similar to that used for the preparation of 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid, 4-(4-{4-[(1-ethyl-4-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidin-1-yl)-2,2-dimethyl-4-oxo-butyric acid was prepared from 1-ethyl-4-methyl-1H-indole-2-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 2,2-dimethylsuccinic anhydride. LCMS for C29H35N3O4 calcd. (m/e) 489, observed 490 (M+H).
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:15]C)=[O:14])=[CH:7][C:6]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[OH-].[Na+]>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([S:17]([CH3:20])(=[O:18])=[O:19])[C:13]([OH:15])=[O:14])=[CH:7][C:6]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C(=O)O)S(C)(=O)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
Into 6 ml of methanol were dissolved 300 mg of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionate, 0.7 ml of 1 mol/l aqueous solution of sodium hydroxide were added, and the mixture was stirred for 1 hour at 50° C. The reaction mixture was poured into water and washed with diethyl ether. The aqueous layer was adjusted to pH value of 1 to 2 with 2 mol/l aqueous solution of hydrochloric acid, which was extracted with methylene chloride. The organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the crystals obtained were recrystallized from diethyl ether-ethyl acetate to obtain 218 mg of aimed product as colorless crystals.
Reaction SMILES: BrC1C=CC=[C:6]2[C:11]=1[N:10]=[C:9](C1C=CC=C(F)C=1)[C:8](CN1C(=O)C3C(=CC=CC=3)C1=O)=[CH:7]2.ClC1C(C=O)=CC2C(=C(Cl)C=CC=2)N=1.[Cl:45][C:46]1[C:55]([CH2:56][N:57]2[C:65](=[O:66])[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:58]2=[O:67])=[CH:54][C:53]2[C:48](=[C:49]([Cl:68])[CH:50]=[CH:51][CH:52]=2)[N:47]=1.[Br-]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:45][C:46]1[C:55]([CH2:56][N:57]2[C:65](=[O:66])[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:58]2=[O:67])=[CH:54][C:53]2[C:48](=[C:49]([Cl:68])[CH:50]=[CH:51][CH:52]=2)[N:47]=1.[Cl:68][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:48]=1[N:47]=[C:46]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:11][N:10]=1)[C:55]([CH2:56][NH2:57])=[CH:54]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cccc(Br)c2nc1-c1cccc(F)c1
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)N1Cc1cc2cccc(Cl)c2nc1Cl
Agent: O=Cc1cc2cccc(Cl)c2nc1Cl
Solvent: C1COCCO1
Product: NCc1cc2cccc(Cl)c2nc1-c1ccccn1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
2-((2,8-Dichloroquinolin-3-yl)methyl)isoindoline-1,3-dione was prepared in the similar manner as 2-((8-bromo-2-(3-fluorophenyl)quinolin-3-yl)methyl)-isoindoline-1,3-dione from 2,8-dichloroquinoline-3-carbaldehyde. A mixture of 2-((2,8-dichloroquinolin-3-yl)methyl)isoindoline-1,3-dione (71 mg, 0.2 mmol), 2-pyridylzine bromide (0.5 M, 0.8 mL, 2.0 eq) and tetrakis(triphenylphosphine) palladium (11 mg, 5%) in dioxane (3 mL) was purged with N2 and heated to 65° C. After 12 h, the reaction was cooled to it and quenched with NH4Cl solution. After work up, The residue containing a mixture of 2-((8-chloro-2-(pyridin-2-yl)-quinolin-3-yl)methyl)isoindoline-1,3-dione and 2-((8-chloro-2-(pyridin-2-yl)-quinolin-3-yl)methyl)carbamoyl)benzoic acid was treated with NH2NH2 (31 μL) in EtOH (1 mL) at reflux. After usual work up, the residue was purified on column chromatography on silica gel (DCM/MeOH/Et3N, 20/1/0.1) to give a pale yellow solid as (8-chloro-2-(pyridin-2-yl)quinolin-3-yl)methanamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (d, J=8.0 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.13 (s, 3H). Mass Spectrum (ESI) m/e=270 (M+1).
Reaction SMILES: BrC[C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13].C([O-])(=O)C.[K+].O.[C:20]([O:23][CH2:24]C)(=[O:22])[CH3:21]>CN(C)C=O>[C:20]([O:23][CH2:24][C:8]1[S:7][C:6]2[CH:10]=[C:11]([F:12])[CH:3]=[C:4]([F:13])[C:5]=2[CH:9]=1)(=[O:22])[CH3:21]
Reactant: Fc1cc2sccc2c(F)c1CBr
Reactant: CCOC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc2c(F)cc(F)cc2s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzo[b]thiophene in 5 ml of N,N-dimethyl-formamide is added 0.23 g of potassium acetate, and the resulting mixture is stirred at 60° C. for one hour. The temperature of the thus stirred mixture is lowered to room temperature, and 10 ml of water and 10 ml of ethyl acetate are added thereto. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under educed pressure, to obtain 0.14 g of colorless, oily acetoxymethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.[Cl:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[C@H:40]([NH:45][S@@:46]([C:48]([CH3:51])([CH3:50])[CH3:49])=[O:47])[C:41]([F:44])([F:43])[F:42].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:28]=[CH:27][C:26]=1[C@H:40]([NH:45][S@@:46]([C:48]([CH3:51])([CH3:50])[CH3:49])=[O:47])[C:41]([F:44])([F:43])[F:42]
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(F)(F)F
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(OCCn3nc(-c4ccc([C@H](N[S@](=O)C(C)(C)C)C(F)(F)F)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (255 mg, 769 μmol), (R)—N—((S)-1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (260 mg, 591 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (43.3 mg, 59.1 μmol), cesium carbonate (771 mg, 2365 μmol) in 1,4-dioxane (3 mL) and water (0.75 mL) was sparged with argon for 5 minutes then heated to 90° C. with stirring for 2 hours The reaction was then partitioned between 9:1 CHCl3/IPA (25 mL) and 5% NaHCO3 (10 mL). The organic layer was then dried over MgSO4, concentrated, then purified on silica (40 g) eluting with 2 to 3% MeOH/DCM. Product was isolated as an off white solid from ACN. MS (ESI pos. ion) m/z: 609 (MH+); calc'd for C28H28ClF3N4O4S: 608. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 9 H) 3.87 (d, J=8.02 Hz, 1 H) 3.91 (s, 3 H) 4.66 (t, J=5.38 Hz, 2 H) 4.80 (t, J=5.28 Hz, 2 H) 5.46-5.56 (m, 1 H) 6.68 (d, J=5.28 Hz, 1 H) 7.00-7.09 (m, 2 H) 7.34 (d, J=2.35 Hz, 1 H) 7.52 (d, J=8.22 Hz, 1 H) 7.59-7.66 (m, 2 H) 7.84 (d, J=1.96 Hz, 1 H) 7.99 (d, J=9.19 Hz, 1 H) 8.64 (d, J=5.28 Hz, 1 H). 19F NMR (377 MHz, CHLOROFORM-d) δ ppm −73.59 (d, J=8.01 Hz, 3 F).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[C:18]([OH:22])(=[O:21])[CH2:19][SH:20]>C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([S:20][CH2:19][C:18]([OH:22])=[O:21])[N:3]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Reactant: O=C(O)CS
Solvent: CC(=O)O
Product: O=C(O)CSC1c2ccccc2C(=O)N1Cc1cccs1
Yield: 83.2 %

Procedure:
To a solution of compound 12 (5.45 gm, 22.2 mmol) in acetic acid (50 mL) at room temperature was added thioglycolic acid (1.85 mL, 26.7 mmol) and the resulting reaction mixture was allowed to stir at reflux for 18 hours. The reaction mixture was concentrated in vacuo and triturated with ethyl ether to provide 5.9 gm of 15 as a white solid (7.08 gm theoretical, 83% yield).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cn1cncc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (10 g, 62 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 20.7 mL, 62 mmol). After stirring at room temperature for 15 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-methoxy-N-methylbenzamide (9.46 mL, 62 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature. After standing for one night at room temperature, the mixture is worked-up by addition of water (150 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (2×100 mL), the organic layers were washed with water (100 mL) then dried over MgSO4 and concentrated in vacuo. The resulting orange solid was washed with pentane to afford (1-methyl-1H-imidazol-5-yl)(phenyl)methanone [8.50 g, yield 66%; HPLC/MS: m/z=187 (M+H); log P(HCOOH)=0.79].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[N:29]([CH3:31])[CH3:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].C(=O)(O)[O-].[Na+].[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)#[N:38]>C(OCC)(=O)C>[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([NH:1][C:2]2[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=2[N:29]([CH3:31])[CH3:30])[C:5]([NH:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:19])[F:17])=[CH:10][C:9]=2[CH3:25])=[O:6])=[O:44])=[CH:41][CH:40]=1)#[N:38]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c(N)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c(NC(=O)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
3-Amino-4-dimethylamino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (200 mg, 0.44 mmol) (see Example I9) was dissolved in a biphasic mixture of ethyl acetate (4 ml) and aqueous sodium bicarbonate (1N) (4 ml). 4-Cyano-benzoyl chloride (75 mg, 0.44 mmol) was added under vigorous stirring. The reaction mixture was stirred for 18 hours at ambient temperature. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography over silica gel (eluent:cyclohexane/ethyl acetate ratio 1:1) gave Compound No. A16 of Table A below (244 mg, 95% yield).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:42]([O:44][C:45](=[O:58])[CH:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=1)[CH3:43].CCOC(/N=N/C(OCC)=O)=O>>[CH2:42]([O:44][C:45](=[O:58])[CH:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:5]=2)=[CH:50][CH:49]=1)[CH3:43]
Reactant: OCCC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCC(c2ccccc2)c2ccc(-c3ccccc3)cc2)cc1)OCC
Yield: 90.4 %

Procedure:
Reaction of 3-biphenyl-4-yl-3-phenyl-propan-1-ol (145 mg, 0.5 mmol), triphenylphosphine (145 mg, 0.55 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (140 mg, 0.6 mmol) and diethylazodicarboxylate (0.09 mL, 0.55 mmol) in an identical manner to Example 1 gave the title compound (230 mg).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Cl-].C(C[NH3+])C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[O:4]=[C:3]1[NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:2]1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A solution of chloroacetyl chloride (31.2 g) in chloroform (100 ml) was added dropwise to a mixture of 2-aminophenol (25 g), benzylmethylammonium chloride (52.4 g), sodium bicarbonate (77 g) and chloroform (500 ml) which was cooled in an ice-bath. The mixture was stirred for 1 hour and allowed to warm to ambient temperature. The mixture was heated to 55° C. for 5 hours and then stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and an aqueous solution of potassium carbonate. The organic phase was washed with dilute aqueous hydrochloric acid and with water, dried (MgSO4) and evaporated. The residue was washed with a mixture of hexane and diethyl ether to leave 3-oxo-2,3-dihydro-4H-1,4-benzoxazine (11 g, 32%) m.p. 172°-173° C.
Reaction SMILES: ClC1C=CC2N(C(C[NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19](OC)=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=NN=2)N=1.ClC1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1C(NC(=O)OC(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[N:16]1[C:17]2[C:22](=[N:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH2:12])=[CH:14][CH:15]=1
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Nc1ccnc2cccnc12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (300 mg, 878 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (419 mg, 1097 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (193 mg, 263 μmol), cesium carbonate (1144 mg, 3511 μmol) in dioxane (6 mL) and water (1 mL) was sparged with argon for 10 min then heated to 100° C. for 20 h with stirring. Reaction then partitioned between 9:1 CHCl3/IPA (50 mL) and 1M NaOH (25 mL). Aqueous further extracted with 9:1 CHCl3/IPA (20 mL). Combined organics then dried over MgSO4, concentrated, and purified on 40 g silica eluting with 7>8% of 2M NH3 in MeOH/DCM. Product then further purified on prep HPLC eluting with water/ACN (0.1% TFA). BOC intermediate then stirred as a solution in DCM (1 mL) and TFA (3 mL) for 30 min. Solvents removed under reduced pressure and residue dissolved in MeOH (8 mL) and DCM (8 mL). Solution then stirred with Si-Carbonate from Silicycle (1 g/with a labeled loading of 0.77 mmol/g) for 1 h at 23° C. Suspension filtered and filtrate reduced to a film under reduced pressure. Product was lyophilized from 1:1 ACN/water (1.5 mL) to provide N-((6-(4-(1-aminoethyl)-3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy)-1,5-naphthyridin-4-amine as an off white fluffy solid. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass for C23H21ClN8O: 460.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[C:29](=[O:32])[NH:30][CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[F:22][C:23]1[CH:24]=[C:25]([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[C:29]([NH:30][CH3:31])=[O:32]
Reactant: CNC(=O)c1ccc(B(O)O)cc1F
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)cc1F
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.072 g, 0.243 mmol; see preparation in WO2011143365), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (0.076 g, 0.388 mmol, Combi-blocks), potassium phosphate (0.129 g, 0.607 mmol, Alfa Aesar), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.017 g, 0.024 mmol, Aldrich), water (0.3 mL) and dioxane (1.2 mL) was purged with Argon gas. The mixture was heated at 100° C. for 30 min in microwave reactor, then the heating was stopped and the mixture was cooled to room temperature. The mixture was diluted with saturated Na2CO3 and extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography (12 g, 0%-100% EtOAc-CH2Cl2). The product was further purified by reverse phase HPLC (Shimazu; Gemini 10 μM C18 110A AXIA, 100×50 mm column, 10-55% MeCN in water with 0.1% TFA in 26 min). The collected fractions were neutralized with solid Na2CO3 and extracted with CH2Cl2 three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (73 mg, 73%). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.10 (d, J=4.69 Hz, 3 H) 4.30-4.55 (m, 5 H) 6.63 (d, J=8.80 Hz, 1 H) 6.83 (d, J=7.04 Hz, 1 H) 7.23 (t, J=7.34 Hz, 1 H) 7.37 (d, J=12.32 Hz, 1 H) 7.42 (dd, J=8.02, 1.17 Hz, 1 H) 7.50-7.57 (m, 1 H) 7.61 (d, J=7.82 Hz, 1 H) 7.73 (d, J=8.41 Hz, 1 H) 7.89 (d, J=8.80 Hz, 1 H) 8.28 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.35 Hz, 1 H) 8.64 (d, J=2.35 Hz, 1 H). m/z=414 (M+1).
Reaction SMILES: [H-].[Na+].C(OC([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=O)C1C=CC=CC=1.CI.[CH3:29]N(C)C=O>[Pd].C(O)C>[C:23]([O:22][C:20](=[O:21])[N:19]([CH3:29])[CH:15]1[CH2:16][CH2:17][CH2:18][NH:13][CH2:14]1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a water bath at room temperature, sodium hydride (60% in oil) (0.4 g) was added to a mixture of 3-t-butoxycarbonylaminopiperidin-1-carboxylic acid benzyl ester (compound 25a) (3.3 g), methyl iodide (0.75 mL), and N,N-dimethylformamide (20 mL), and this was stirred at room temperature for four hours. The reaction solution was extracted using ethyl acetate and water, the organic layer was washed with water, and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography using 10% to 20% ethyl acetate/hexane to give an oily substance (3.04 g). A mixture of all of the resulting material with ethanol (20 mL) and 10% palladium on carbon was stirred under hydrogen atmosphere at room temperature for five hours. The catalyst was filtered off, and the filtrate was concentrated to give the title compound (1.82 g).