Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([NH:6][CH2:7][C:8]([F:17])([C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)[CH3:9])(=[O:5])=[O:4].[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>O>[NH2:19][C:20]1[CH:25]=[C:24]([C:13]2[CH:14]=[CH:15][C:10]([C:8]([F:17])([CH3:9])[CH2:7][NH:6][S:3]([N:2]([CH3:18])[CH3:1])(=[O:5])=[O:4])=[CH:11][CH:12]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Temperature: 70 °C

Procedure:
[(Dimethylamino)sulfonyl][2-fluoro-2-(4-iodophenyl)propyl]amine (386, 1.0 mmol, prepared in example 36), 3-aminobenzeneboronic acid (201 mg, 1.3 mmol), potassium carbonate (179 mg, 1.3 mmol), tetrakis(triphenyl phosphine)palladium(0) (58 mg, 0.05 mmol), and dioxane/water (60 mL, 3:1) are mixed together in a 100 mL single neck flask and stirred at 70° C. over night. In the morning, the reaction is cooled to room temperature and poured into H2O, and the desired product is extracted with ethyl acetate. The organic layer is backwashed once with H2O, dried over K2CO3, filtered, and concentrated under reduced pressure. The crude material is purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:47]([NH:54][CH3:55])[CH2:48][N:49]2[CH2:52][CH:51]([OH:53])[CH2:50]2)[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:54]([C@@H:47]([CH:43]1[CH2:46][CH2:45][CH2:44]1)[CH2:48][N:49]1[CH2:50][CH:51]([OH:53])[CH2:52]1)[CH3:55])=[O:15]
Reactant: CN[C@H](CN1CC(O)C1)C1CCC1
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(F)cc1Cl)[C@H](CN1CC(O)C1)C1CCC1
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
DIPEA (0.183 mL, 1.05 mmol) was added to a stirred suspension of 2-chloro-4-fluorobenzoic acid (55 mg, 0.31 mmol) and TBTU (0.101 g, 0.31 mmol) in DCM (1 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound Z2.1) (0.07 g, 0.35 mmol) in DCM (1 mL) was added over 3 min. The ice-bath was removed and the reaction was stirred at rt for 2 h. The reaction mixture was washed with NaHCO3 (8% aq., 3 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (54 mg, 45%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 1.41-2.1, 2.22-2.85, 3.06-3.59, 4.02-4.23, 4.46-4.60, 5.17-5.35, 7.23-7.72. HRMS (M+H)+: calculated 341.1432. found 341.1442.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([N:33]2[C:37](=[O:38])[CH2:36][CH2:35][C@@H:34]2[CH2:39][OH:40])[CH:3]=1.[C:41](Cl)(=[O:43])[CH3:42].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:41]([O:40][CH2:39][C@H:34]1[CH2:35][CH2:36][C:37](=[O:38])[N:33]1[C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO)c(OCc1ccccc1)c2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1CCC(=O)N1c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 23 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of intermediate 192, (R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.045 g, 0.082 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (12.8 μL, 0.180 mmol) and diisopropylethylamine (31.4 μL, 0.180 mmol). The reaction mixture was stirred at 23° C. for 4 h. NaHCO3 (1N in H2O, 30 mL) was then added and the organic material was extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate/Hexanes (1:1) to ethyl acetate 100% as eluent to afford the title compound (0.032 g, 67% yield): 1HNMR 400 MHz (MeOD) δ ppm: 7.48 (3H, m), 7.33 (3H, m), 7.16 (1H, m), 7.03 (1H, m), 5.24 (2H, s), 4.60 (1H, m), 4.55 (1H, m), 4.22 (1H, dd, J=12.0, 4.5 Hz), 4.08 (2H, t, J=5.0 Hz), 3.99 (3H, m), 2.62 (2H, m), 2.44 (1H, m), 2.09–1.92 (5H, m), 1.62 (3H, s), 1.61 (3H, s). LCMS (M+H)+ m/z 593.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:18])[CH:9]=1)=[O:7])C.O.Cl>C(O)C>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[CH:9]=[C:8]2[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cn(C)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
1N Aqueous solution of sodium hydroxide (10 ml) was added at room temperature to a solution of 5-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester (605 mg) in ethanol (10 ml) and stirred at 70° C. for three hours. After completion of the reaction, the reaction solution was cooled to room temperature, water and 1N hydrochloric acid aqueous solution were added and the precipitated solid was collected by filtration to give the titled compound (530 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:31][C@H:30]2[C@@H:25]([O:26][CH:27]([CH:32]=[CH2:33])[O:28][CH2:29]2)[C@H:24]([OH:34])[C@H:23]1[OH:35])[CH:2]=[CH2:3].C([BH3-])#N.[Na+].FC(F)(F)S(O)(=O)=O.O>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:23]([OH:35])[C@@H:24]([OH:34])[C@H:25]([OH:26])[C@@H:30]([CH2:29][O:28][CH2:27][CH:32]=[CH2:33])[O:31]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@@H]2COC(C=C)O[C@H]2[C@H](O)[C@H]1O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC[C@H]1O[C@@H](c2cc(Cc3ccc(OCC)cc3)c(Cl)cc2OCC=C)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
To a solution (4aR,6S,7R,8R,8aS)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-2-vinylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (14, 669 mg, 1.33 mmol) from Step 1 in tetrahydrofuran (13 mL) was added sodium cyanoborohydride (642 mg, 9.71 mmol), molecular sieves (407 mg) and was added cautiously trifluoromethanesulfonic acid. After addition, the mixture was stirred for another 0.5 h, before being poured into H2O. The aqueous phase was extracted with dichloromethane and the combined organic fractions were washed with brine. The organic layer was dried over magnesium sulfate and filtered through a pad of silica gel. The filtrate was evaporated and went to next step.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCBr)cccc21

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,6-dibromohexane (3.95 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-(4-fluorobenzyloxy)-ethanol (5.11 g, 30.0 mmol, from step (i) above) in methylene chloride (60 mL) was cooled to −10° C. Triethylamine (5.0 mL, 36 mmol) was added followed by methanesulfonyl chloride (3.78 g, 33.0 mmol) and the reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was diluted with methylene chloride (200 mL) and the organic phase was washed with water (2×75 mL) and brine (75 mL), dried over MgSO4, and concentrated in vacuo to give 7.16 g (96%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH3:25])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][CH2:19]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][CH2:19][N:29]([CH3:30])[CH3:28])[CH2:12][CH2:11]2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCCOS(C)(=O)=O)CC1
Solvent: CO
Product: CN(C)CCC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 400 mg (corresponds to 0.69 mmol) of crude trans-Methanesulfonic acid 4-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-but-3-ynyl ester in 4 ml of methanol was treated with 1.23 ml (6.88 mmol) Dimethylamine (33% in EtOH, 5.6M) and stirred over night at RT. The reaction was heated at 70° C. for 2 h, cooled, evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 9:1) gave 84 mg (34%) of trans-[4-(4-Dimethylamino-but-1-ynyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 363 (MH+, 1Cl).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)/C=C\C(=O)O)c1

Procedure:
A stirred solution of 1.0 g. of the N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide from Preparation 27 in 25 ml. of toluene was heated on a steam bath, and then 0.32 g. of maleic anhydride was added in one portion. After a few minutes the reaction mixture was cooled and the toluene was removed by evaporation in vacuo. The residue was recrystallized from acetonitrile to give 0.70 g. of the title compound as a white solid, m.p. 76°-78° C. (dec.). The IR spectrum (KBr disc) showed absorptions at 3448, 3279, 2941, 1724, 1639, 1587 and 1563 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.9 (m, 3H), 1.09 (m, 3H), 1.26 (s, 16H), 2.47 (m, 3H, under DMSO-d6), 3.8 (m, 1H), 6.26 (m, 3H), 7.62 (m, 6H) and 10.44 (s, 1H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>CN(C=O)C>[N:1]1([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
To imidazole (7 gm, 103 mmol) suspended in degassed DMF (250 mL) under argon was added NaH 60% dispersion in mineral oil (4.53 gm, 113 mmol) with stirring for 10 minutes. A solution of 4-bromomethyl benzonitrile in 50 mL of DMF was added and the reaction was stirred for 16 hrs. The reaction was quenched with the addition of 20 mL of water and the solvent was removed in vacuo. The residue was suspended in methylene chloride (500 mL) and extracted 3 times with water (200 mL) and the organic layer was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was chromatographed on silica gel with methylene chloride to remove the oil followed by 95:5 methylene chloride: methanol. The resulting fractions where reduced to a small volume in vacuo and the product spontaneously crystallized. The crystals were filtered to give the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added isopropylamine (18 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (0.096 g, 0.30 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4), filtered and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (51 mg, 65%) as a colorless oil. MS: m/e=369.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(N3CCNCC3)cc1)nn2-c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nccc2c1c(-c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (260 mg) and triethylamine (112 mg) in dichloromethane (5 mL) was added methanesulfonyl chloride (99.0 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and diluted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (240 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[C:5]([CH3:11])[O:4][N:3]=1.CN(C=O)C.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:26]([F:50])[CH:25]=1>ClCCCl>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH:36]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:37]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[O:38])[CH2:32][CH2:31]3)=[C:26]([F:50])[CH:25]=2)=[O:10])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: Cc1noc(C)c1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of (3,5-dimethyl-isoxazol-4-yl)-acetic acid (1.0 mmol) and DMF (0.050 mL) in DCE (10 mL) was treated with (COCl)2 (10 mmol) dropwise, and was stirred at rt for 1 h. The mixture was concentrated and dried under vacuum. The residue was diluted with DCE (10 mL) and 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and TEA (2.0 mmol) were added. The mixture was stirred at rt for 16 h, then was washed with H2O (10 mL). The organic layer was concentrated, and the residue was purified by PTLC to provide the title compound (78 mg, 45%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28. m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 7.59-7.25 (m, 6H), 7.09-6.98 (m, 1H), 6.68-6.57 (m, 1H), 4.21 (s, 1H), 3.50-3.36 (m, 4H), 3.35-3.15 (m, 2H), 3.13-3.00 (m, 4H), 2.73-2.60 (m, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 1.16-1.06 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18](O)=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH2:24])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: N
Solvent: C1CCOC1
Product: C[C@@H](C(N)=O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of (S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.65 g, 0.012 mole) and 1,1'-carbonyldiimidazole (1.96 g, 0.0121 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, liquid ammonia (50 ml) was added, the mixture was allowed to warm to room temperature and was stirred overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was partitioned between water (100 ml) and ethyl acetate (100 ml). The insoluble solid was collected by filtration (1.38 g). The layers were separated, the aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed twice with water, twice with a 5% potassium hydroxide solution and twice again with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to gibe 1.9 g of solid. The 3.28 g (91 % yield) of solids were combined and dissolved in hot methanol, filtered hot, cooled to room temperature and water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water and dried under high vacuum at room temperature to give 2.50 g of title compound, mp. 202°-204° C.
Reaction SMILES: [CH2:1]([C:3]1[N:16]=[C:6]2[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][CH:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:23]([CH2:42][CH2:43][CH3:44])[CH:22]=1.CCOC(C)=O>CN(C=O)C>[C:27]([CH:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:25][C:24]1[CH:40]=[CH:41][C:21]([CH2:20][N:16]2[C:6]3=[N:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:22][C:23]=1[CH2:42][CH2:43][CH3:44])([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: CCCc1cc(CBr)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Reactant: CCc1nc2[nH]c(C(=O)OC)cc(C)c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OC)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a 25 mL round bottom flask were placed 41.8 mg (0.19 mmol) of methyl 2-ethyl-7-methylimidazo[4,5-b]pyridine-5-carboxylate (the product of Step G of this Example) and a 60% oil dispersion of NaH (5 mg, 0.21 mmol). The flask was evacuated and filled with nitrogen. Dry DMF (2 mL) was added to the mixture dropwise at 0° C. The solution was stirred at rt for 5 minutes. To the solution was added 80 mg (0.19 mmol) of tert-butyl 2-(4-bromomethyl-2-propyl- phenoxy)-2-phenylacetate (Step O) in dry DMF (2 mL) at rt. After the solution was stirred at rt for 15 hours, it was poured into EtOAc (10 mL) and washed with H2O and brine, and dried over anhydrous MgSO4. Concentration followed by purification by flash chromatography (hexane: EtOAc=2:1) afforded 63.6 mg of the title compound as a colorless glass.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>CO.[Pd]>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(N)cn1
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of 0.312 g (1.87 mmol) of the above nitro compound and 0.205 g of 10% Pd/C in methanol (40 mL) was stirred under hydrogen (25 in/Hg) for 5 hrs. The reaction mixture was filtered through celite, and the solvent was concentrated, to give 0.236 g (92% yield) of N2,N2-dimethyl-2,5-pyridinediamine: 1H NMR (CDCl3) δ7.78 (d, J=2.9 Hz, 1H), 6.98 (dd, J=8.8, 2.9 Hz, 1H), 6.45 (dd, J=8.8, 0.5 Hz, 1H), 2.99 (s, 6H); LCMS (APCI+) m/z: 138 (MH+, 100%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.82 (1 H, s), 8.35 (1 H, d, J=2.1 Hz), 8.27 (1 H, s), 8.13 (1 H, s), 7.99-8.03 (1 H, dd, J=2.1 and 8.1 Hz), 7.81-7.84 (1 H, d, J=8.7 Hz), 7.76 (1 H, s), 7.66-7.68 (2 H, m), 7.46-7.49 (1 H, d, J=9.0 Hz), 6.76-6.80 (1 H, d, J=9.3 Hz), 4.40 (1 H, m), 2.32-2.34 (2 H, m), 2.17 (3 H, brs), 1.87-1.97 (2 H, m), 1.71-1.76 (2 H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0819.