Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1B1OC(C)(C)C(C)(C)O1.CCN(C(C)C)C(C)C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1nc(Br)c(F)cc1N
Reactant: CC1(C)OB(c2c(F)cccc2F)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(-c2c(F)cccc2F)c(F)cc1N
Temperature: 100 °C
Yield: 74.4 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, methyl 3-amino-6-bromo-5-fluoropyridine-2-carboxylate (99.6 mg, 0.400 mmol) was added, followed by 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Combi-Blocks, 190 mg, 0.80 mmol), and bis(tri-tert-butylphosphine)palladium (40.9 mg, 0.080 mmol). The vial was sealed with a PTFE-lined septum, evacuated and backfilled with nitrogen three times. 1,4-Dioxane (2.0 mL) was added via a syringe, followed by DIPEA (0.14 mL, 0.80 mmol) and deoxygenated water (0.05 mL). The mixture was heated at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and washed with water (40 mL) and brine (40 mL), then dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a white solid (84.0 mg, 74%). LCMS calc. for C13H10F3N2O2(M+H)+: m/z=283.1. found 283.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:34][C:33]([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:32][CH:31]=1)CCC.CN(C)C=O>O.[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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:30]3[O:34][C:33]([Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[N:32][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl) oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine) palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl) oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(tri isopropylsilyl) oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(N(C(C)C)CC)(C)C>>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: CCN(CC)CCBr
Reactant: Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 150 °C

Procedure:
Cyclopropanecarboxylic acid [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (0.05 g, 0.17 mmol), 2-bromo—N,N-diethylethylamine hydrobromide (0.133 g, 0.511 mmol) and diisopropylethylamine (0.089 mL, 0.511 mmol) were added to a microwave tube and the mixture was heated for 10 min at 150° C. The mixture was filtered and purified by preparatory LCMS. LCMS Method: 2: RT: 2.07 min; MI: 393 [M+1]. NMR (DMSO, 300 MHz): 0.81 (d, 4H), 1.10 (t, 6H), 2.04 (brs, 1H), 2.89 (m, 6H), 3.33 (t, 2H), 6.75 (d, 2H), 7.20 (dd, 1H), 7.53 (m, 1H), 7.64 (m, 1H), 7.92 (d, 2H), 8.18 (s, 1H), 11.00 (s, 1H)
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[S:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=S)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1C(=S)NC(c2ccccc2)c2cc3c(cc21)OCO3
Reaction time: 4 h

Procedure:
A solution of 30 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)thiourea, 27.6 mls. of benzaldehyde, and 2 mls. of methanesulphonic acid in 500 ml. of toluene is refluxed under a Dean Stark water separator for 4 hours, during which 2 ml. water is collected. The filtered solution is then evaporated to yield a powder. This product is recrystallized from dioxane and water to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinthione, m.p. 215°-218°C.
Reaction SMILES: C(O[C:6]([N:8]1[C:20]2[C:11](=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:10]([CH2:22][Cl:23])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32]C(O)=O)=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[Cl:23][CH2:22][CH:10]1[C:11]2=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=[C:20]2[N:8]([C:6](=[O:7])/[CH:32]=[CH:31]/[C:30]2[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:9]1)[N:16]=[CH:15][CH:14]=[CH:13]3
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ncccc21
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(O)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
A suspension of 16 (0.10 g, 0.30 mmol) in dioxane (5 mL) was saturated with HCl, stirred at r.t. over 5 h and evaporated. 4-Methoxycinnamic acid (predominantly trans) (0.064 g, 0.36 mmol), EDCI (0.29 g, 1.50 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 3 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (CH2Cl2/MeOH; 93:7) followed by recrystallisation (CH2Cl2/Et2O) gave 18e (0.02 g, 17%) as a yellow solid: mp 208–211° C.; 1H NMR [(CD3)2SO]δ 9.96 (bs, 1 H), 8.73 (d, J=3.3, 1 H), 8.35 (d, J=7.7, 1 H), 8.18 (bs, 1 H), 7.78 (d, J=8.7, 2 H), 7.67 (d, J=15.3, 1 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.08 (d, J=15.4, 1 H), 7.01 (d, J=8.7, 2 H), 4.54 (dd, J=10.3, 9.5, 1 H), 4.45 (m, 1 H), 4.27 (m, 1 H), 3.99 (dd, J=11.1, 3.2, 1 H), 3.88 (dd, J=11.1, 7.3, 1 H), 3.82 (s, 3 H). C22H20ClN2O3 requires M+H 395.1163, 397.1133. Found (FAB) 395.1161, 397.1169.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:42]([C:33]3[CH:34]=[CH:35][C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=3)=[O:43])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.10 g) was dissolved in dichloromethane (30 ml), and potassium carbonate (0.82 g) was added. Then, a solution of 2-naphthoyl chloride (0.33 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.25 g of 4-amino-5-chloro-2-methoxy-N-(1-(4-(2-naphthoylamino)butyl)piperidin-4-ylmethyl)benzamide.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:10]=1[Cl:27])C1C=CC=CC=1>Br.C(O)(=O)C>[Cl:27][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Clc1cc(OCCOCCc2ccccc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(OCCOCCc2ccccc2)cc1Cl
Yield: 76 %

Procedure:
The 1-benzyloxy-2-chloro-4-(2-phenethyloxyethoxy)-benzene obtained according to the preceding paragraph was stirred in 20 ml of 48% hydrogen bromide in glacial acetic acid at 25° C. for 30 minutes. The solution was evaporated to dryness and the residue was partitioned between 2N aqueous sodium hydroxide and diethyl ether. The aqueous phase was acidified to pH 6 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, filtered and evaporated to give 2.06 g (76%) of 2-chloro-4-(2-phenethyloxyethoxy)phenol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[C:1]#[C:2][CH3:3])[CH:19]=[CH:20][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC#C[Mg]Br
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: CC#CC(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 L round bottom flask was charged with 1-propynylmagnesium bromide (0.5 M in THF) (available from Aldrich) (245 mL, 123 mmol) and cooled to −78° C. To the cold slurry was added a solution of 3-benzyloxybenzaldehyde (available from Aldrich) (20.0 g, 94.2 mmol) in THF (30 mL) over 15 minutes. The mixture was stirred for 30 minutes at −78° C., the cooling bath was removed, and stirring was continued for 1 hour at ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to afford 93.A (23.1 g, 97% yield) as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.Cl.[CH3:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:10]=1[O:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([CH2:12][O:11][C:10]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:9]=3[CH3:8])[CH2:14]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc(C)c1OC[C@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OC[C@H]1CCCN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylcarbonyl chloride (1.7 mL, 18 mmol) was added dropwise during 15 minutes to an ice cold mixture containing (S)-3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride (4.4 g, 17 mmol), aqueous sodium bicarbonate (75 mL), and ethyl acetate (100 mL). After the addition was complete, the reaction was stirred at room temperature for 1 hour, and the resulting ethyl acetate layer was separated and concentrated. The residue was dissolved in dry tetrahydrofuran (125 mL) under a dry nitrogen atmosphere and a 1M solution of lithium aluminum hydride in tetrahydrofuran (18.9 mL) was added dropwise. When the addition was complete, the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature. Solid sodium sulfate decahydrate (10 g) was slowly added with stirring and the mixture was filtered. The filtrate was concentrated and chromatographed on silica gel, eluting with acetone/hexanes (1:3) to give (S)-1-cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)-piperidine as an oil.
Reaction SMILES: [Cl-:1].C[O:3][C:4](=[O:16])[CH2:5][N:6]1[CH:10]=[CH:9][N+:8]([CH2:11][C:12](=[O:15])[O:13]C)=[CH:7]1.Cl>>[Cl-:1].[C:12]([CH2:11][N:8]1[CH:9]=[CH:10][N+:6]([CH2:5][C:4]([OH:16])=[O:3])=[CH:7]1)([OH:15])=[O:13]
Reactant: COC(=O)Cn1cc[n+](CC(=O)OC)c1
Agent: Cl
Agent: [Cl-]
Product: O=C(O)Cn1cc[n+](CC(=O)O)c1
Yield: 87.7 %

Procedure:
To 1,3-bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9; 41.00 g, 164.88 mmol, 1 eq.) was added 37% aq. HCl (30.03 mL, 362.74 mmol, 2.2 eq.). The mixture was stirred under reflux for 0.5 hour. The mixture was concentrated and the remaining solid was washed with acetone (2×200 mL) and Et2O (3×200 mL). Drying in in vacuo gave 10 (31.89 g, 144.55 mmol, 87.7%) as a white solid.
Reaction SMILES: [CH:1]1([C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:15][CH:14]=1>CS(C)=O.[Cl-].[Na+].O>[CH:1]1([C:4](=[O:8])[CH:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])=[CH:17][CH:18]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1)C(=O)C1CC1
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2.61 g (24.0 mmol) 3-cyclopropyl-3-oxopropanenitrile in 150 mL DMSO was added 1.01 g (25.2 mmol) 60% NaH in oil. After 1 hour, 3.50 g (12.0 mmol) 4'-bromomethyl-2-nitrobiphenyl was added all at once to the solution. After 3 hours, the solution was poured into brine and extracted 3 times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 3/40/57 EtOAc/CH2Cl2/hexanes to give 1.29 g (34% yield) of the title compound as a yellow glass. Rf 0.13 in 3/40/57 EtOAc/CH2Cl2/hexanes, visualized by UV and ammonium molybdate/ceric sulfate stain; Rf of the dialkylated material is 0.19 in the same solvent mixture.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:29].[K+].OO>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]([NH2:15])=[O:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(N)=O)c1ccc(F)cc1
Temperature: 65 °C
Yield: 57.9 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1; 0.5 g, 1.3 mmol) in MeOH (50 ml), was added a 25% aqueous solution (2 ml) of KOH (400 mg) at 25° C., followed by the addition of 0.1 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=30:1) to give the title compound (0.30 g, 60%). 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=7.0 Hz, 1H), 7.90 (br s, 1H), 7.35-7.32 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.00-6.95 (m, 2H), 6.00 (br s, 1H), 5.66 (br s, 2H), 5.21-5.17 (m, 1H), 1.86-1.82 (m, 1H), 1.54 (d, J=6.8 Hz, 3H), 0.96-0.92 (m, 2H), 0.69-0.67 (m, 2H). MS: Calcd.: 398. Found: [M+H]+ 399.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.74 g of 5% palladium-carbon was added to a mixed solution of 56 mL of methanol and 56 mL of ethyl acetate containing 3.7 g of tert-butyl 2-nitro-4-((E)-2-phenylvinyl)benzoate and stirred under hydrogen atmosphere at room temperature for 2 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 3.4 g of tert-butyl 2-amino-4-phenethylbenzoate as white solid.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[K].[CH3:21][NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH:23]1([N:22]([CH3:21])[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=[CH:2]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(Cn2cnc3cnccc32)cc1
Reactant: CNC1CCCCC1
Agent: [K]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(Cn2cnc3cnccc32)cc1)C1CCCCC1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A stirred suspension of 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)benzoic acid, potassium salt (0.78 g, 0.0027 mol) in dry dimethylformamide (5 ml) was treated with N-methylcyclohexylamine (0.36 g, 0.0032 mol) and triethylamine (0.54 g, 0.0054 mol). The reaction mixture was cooled to -5° C. and then treated with diphenylphosphoryl azide (0.81 g, 0.0030 mol). The resulting mixture was allowed to warm up to room temperature and stirred for an additional 15 hours. The solvent was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 5% ethanol in chloroform) and recrystallized from ethyl acetate to yield N-cyclohexyl-N-methyl-4-(1H-imidazo[4,5-c]pyridin-1-yl-methyl)benzamide as a colorless crystalline solid, having a melting point of 132°-134° C. and the following physical characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:11]([C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1nc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1
Product: CC(C)(C)c1nc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a yellow solid, MS: m/e=277.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and phenylacetylene.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:19])(=[O:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[C:38]=1[C:39]([NH2:41])=[O:40]>CC(N(C)C)=O.O>[C:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:41][C:39](=[O:40])[C:38]4[C:37](=[CH:45][C:44]([O:46][CH3:47])=[CH:43][C:42]=4[O:48][CH3:49])[N:36]=3)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
A mixture of 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.580 g, 2.20 mmol), NaHSO3 (0.260 g, 2.40 mmol), and p-TsOH (0.039 g, 0.20 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.400 g, 2.20 mmol) in DMA (15 mL). The reaction was stirred at 120° C. for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.400 g, 46%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.78 (br s, 1H), 8.10 (d, J=8.9 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 4.01-4.64 (m, 2H), 3.71-3.95 (m, 8H), 2.87-3.07 (m, 2H), 2.06 (s, 3H), 1.25 (d, J=6.2 Hz, 6H). ESI MS m/z 437 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:22]([C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)[C@H](CCCCN)N(C(=O)OC(C)(C)C)C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and NE-(tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.40 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCN=C=O
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.130 g 0.38 mmoles) and ethyl isocyanate (260 mg, 10 fold excess) the title compound was isolated as a white solid. Yield; 38 mg (25%); (M+H)=414.4