Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[C:3]([CH:9]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: Brc1cncnc1
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN(C)C(=O)c1cc(Br)ccc1Nc1cncnc1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A vial is charged with 120 mg (0.49 mmol) of 2-amino-5-bromo-N,N-dimethyl-benzamide, 11.4 mg (12 μmol) of tris(dibenzylideneacetone)dipalladium(0), 15.9 mg (27 μmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 290 mg (0.89 mmol) of cesium carbonate, and 159 mg (1.00 mmol) of 5-bromo-pyrimidine. The vial is flushed with nitrogen and 2 mL of anhydrous 1,4-dioxane are added. The vial is sealed and heated to 100° C. for 17 h. The resulting mixture is diluted with methanol and dichloromethane and filtered over a 0.45 μm PTFE syringe filter. The filtrate is evaporated and the residue purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 10% v/v of methanol in hexanes to afford 115.6 mg (0.39 mmol, 80%) of 5-bromo-N,N-dimethyl-2-(pyrimidin-5-ylamino)-benzamide as an ivory solid. 1H-NMR (500 MHz, d6-DMSO): δ 8.66 (s, 1H), 8.48 (s, 2H), 8.13 (s, br., 1H), 7.51 (dd, 1H), 7.43 (d, 1H), 7.23 (d, 1H), 2.86 (s, 3H), 2.81 (s, 3H); MS: m/z 321.0+323.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28]C)=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([OH:28])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCOCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)quinoxaline-6-carboxylate (100 mg) in methanol (20 mL) was added sodium hydroxide (40 mg, 1.00 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with hydrochloric acid (3 N) and the product was precipitated to afford 2-(4-fluorophenyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (52 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 2 h

Procedure:
Pd on C 10% (0.3% p/p) was added to a solution of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (1 eq) in a mixture (1:1 ratio) MeOH:EtOAc (0.03 M). The atmosphere in the reaction vessel was charged with H2 (1 atm.) and the reaction stirred vigorously for 2 h. At this time, the reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (quant); MS (ES+) m/z 278 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([NH:18][C:19]3[N:28]=[C:27]4[C:22]([C:23](=[O:40])[N:24]([C:32]5[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:39])[C:25]5[N:26]4[CH:29]=[CH:30][N:31]=5)=[CH:21][N:20]=3)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[N:24]1[C:23](=[O:40])[C:22]2[CH:21]=[N:20][C:19]([NH:18][C:12]3[CH:13]=[N:14][C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[CH:11]=3)=[N:28][C:27]=2[N:26]2[CH:29]=[CH:30][N:31]=[C:25]12.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(Nc3ncc4c(=O)n(-c5c(F)cccc5Cl)c5nccn5c4n3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cnc(Nc3cnc4c(c3)CNCC4)nc2n2ccnc2n1-c1c(F)cccc1Cl

Procedure:
A mixture of Example 277A (54.6 mg, 0.097 mmol) and trifluoroacetic acid (0.075 mL, 0.970 mmol) in CH2Cl2 (3 mL) was stirred overnight. The solids were filtered, rinsed with CH2Cl2, and dried to provide the title compound as a trifluoroacetic acid salt. 1H NMR (400 MHz, CD3OD) δ 3.29-3.26 (m, 2H), 3.68 (t, J=6.4 Hz, 2H), 4.55 (s, 2H), 7.11 (d, J=1.9 Hz, 1H), 7.44-7.35 (m, 1H), 7.56-7.53 (m, 1H), 7.66-7.60 (m, 1H), 7.91 (d, J=1.9 Hz, 1H), 8.38 (bs, 1H), 8.93 (bs, 1H), 9.26 (s, 1H). MS (ESI+) m/z 463.2 (M+H)+.
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]#[N:8])=O.[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][C:24](=O)[CH2:23]2)[CH:18]=[CH:19][C:20]=1[Cl:21]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]([CH2:6][C:7]#[N:8])[CH2:23]2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC1=Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of diethyl cyanomethyl phosphonate EtO2POCH2CN (0.324 mL, 2 eq) in THF (2 mL) was added sodium hydride (60 mg, 60% in oil) in portions. After 30 minutes, 4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2(1H)-one (beta-tetralone) (291 mg, 1 mmol) was added as a solution in THF (3 mL). After the mixture was stirred for two hours at 0° C., the reaction was quenched with ammonium chloride solution, extracted with MTBE, dried over sodium sulfate and evaporated. The residue was separated on silica to give the unsaturated nitrile (0.24 g, 77%) as a pale-green oil. GC-MS Rt=14.59 min, m/z=313 (M+). 1H NMR (CDCl3, δ): 7.37 (d, J=8.3 Hz, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 7.00 (dd, J=2.1, 8.3 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.64 (bs, 1H), 4.17 (t, J=8.1 Hz, 1H), 3.21 (bs, 2H), 2.69 (dd, J=6.9, 17.3 Hz, 1H), 2.52 (dd, J=8.4, 17.2 Hz, 1H). 13C NMR (CDCl3, δ, mult): 143.9(0), 135.2(0), 132.9(0), 132.5(0), 130.7(1), 130.5(1), 130.0(1), 128.2(1), 127.7(1), 127.5(1), 126.8(1), 126.4(1), 116.5(0), 43.1(1), 35.1(2), 25.1(2).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(OCC)C>[C:16]([O:15][C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To the suspension of 10 g (76.2 mmol ) of L-leucine in 140 mL of diethyl ether was added 80 mL of 10% NaOH. After all solid dissolves, 20 mL (87.1 mmol) of BOC2O was added to the reaction mixture. The resulting reaction mixture was stirred at 23° C. for 12 h. After this period, the layers were separated and the aqueous layer was acidified to pH 1 by careful addition of 1 N aqueous HCl at 0° C. The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined and washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide title product which was used directly for next reaction without further purification (yield, 97%). 1H NMR (400 MHz, CDCl3) δ 4.89 (broad d, 1H, J=8.3 Hz), 4.31 (m, 1H), 1.74–1.49 (m, 3H), 1.44 (s, 9H), 0.95 (d, 6H, J=6.5 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[CH2:10])[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[CH2:10])[C:7]([Cl:13])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: C=C(C(=O)O)c1ccco1
Product: C=C(C(=O)Cl)c1ccco1

Procedure:
Furylacrylic acid (marketed by Aldrich) and excess thionyl chloride, SOCl2, are first reacted together at reflux for several hours in order to obtain furylacrylic acid chloride.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([O:23][CH3:24])[CH:10]=1)(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:10][C:11]=1[O:23][CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(CCCOS(C)(=O)=O)ccc1OCc1ccccc1
Reactant: c1c[nH]cn1
Product: COc1cc(CCCn2ccnc2)ccc1OCc1ccccc1
Yield: 57 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(4-benzyloxy-3-methoxyphenyl)propyl methanesulfonate was reacted with imidazole to obtain 1-[3-(4-benzyloxy-3-methoxyphenyl)propyl]imidazole as an oil. The yield was 57%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[C:17]([NH2:30])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:30][C:17]1[C:18]([C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[O:29])=[CH:19][CH:20]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
4-[6-Amino-5-(2-fluoro-benzoyl)-pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (269.6 mg, 0.6504 mmol, Example 8) was dissolved in dichloromethane (5 mL), cooled to 0° C. and treated with trifluoroacetic acid (2.5 mL). After stirring ˜30 minutes, the reaction mixture was concentrated in vacuo. The salt was then neutralized with saturated sodium carbonate (˜3 mL), extracted with ethyl acetate/methylene chloride (˜50 mL), washed with saturated sodium chloride (˜3 mL), dried over sodium sulfate and evaporated in vacuo to give [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone as an off-white solid (200 mg, 0.636 mmol, 98 % yield).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[C-]#N.[Na+].CCO.[CH3:23][N:24](C=O)[CH3:25]>CCOC(C)=O>[CH3:23][N:24]([CH3:25])[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Temperature: 130 °C
Yield: 27 %

Procedure:
To a solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (294 mg, 1.31 mmol, as prepared in the previous step) in 8 mL EtOH-DMF (v/v) was added NaCN (128 mg, 2.6 mmol). The reaction was heated to 130° C. in a sealed tube for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (2×50 mL). Chromatography (50% EtOAc-hexane) of the crude product afforded 88 mg (27%) the title compound as well as 78 mg (24%) (1-(5-ethoxy-2-nitro-phenyl)-piperidine as yellow solids. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O2, 250.1 (M+H), found 250.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[Cl:21][C:15](=[O:17])[CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (3.84 g, 15.78 mmol) (prepared using M from ethyl 2-(piperidin-4-yl)acetate (Oakwood), Z) in DCM (79 mL) at ambient temperature were added oxalyl chloride (1.658 mL, 18.94 mmol) and DMF (0.115 g, 1.58 mmol). The reaction mixture was stirred at ambient temperature for about 3 h. The solvent was removed under reduced pressure to afford tert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (4.13 g, 100%) as a light yellow solid. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][Cl:13])=[C:6]([O:14][CH3:15])[CH:5]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:10][CH2:11][CH2:12][Cl:13])=[CH:8][C:9]=1[N+:24]([O-:26])=[O:25]
Reactant: COC(=O)c1ccc(OCCCl)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 85 %

Procedure:
The intermediate 4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester (2.7 g, 11.03 mmol) was taken in acetic acid (30 mL) and acetic anhydride (6 mL) was added. The solution was cooled to 0° C. and 90% nitric acid (2 mL) was added. The reaction mixture was stirred for 10-15 minutes at ambient temperature, then heated to 50° C. for 2 h. Completion of the reaction was monitored by TLC. The reaction mixture was cooled and was poured on to crushed ice. The precipitate formed was filtered and was dried to afford the pure 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (2.73 g, 85%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.35 (s, 1H), 4.42 (t, 2H), 4.10-3.90 (m, 5H), 3.80 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.CCOCC>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(Br)cn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccc(Br)cn2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
5-bromopicolinonitrile (D9) (43.6 g, 0.238 mol) was suspended in diethyl ether (1.3 L) and the resulting mixture was cooled to −78° C. Titanium (IV) isopropoxide (74.4 g, 0.262 mol) was added dropwise and the reaction mixture was stirred for 5 min. Ethylmagnesium bromide 1M in diethyl ether (525 ml, 0.525 mol) was added dropwise and the resulting reaction mixture was stirred for 30 mins at −78° C. The reaction mixture was allowed to warm to room temperature for 1 hour then boron trifluoride etherate (107 ml) was added dropwise. After stirred at room temperature for 2 hours, the reaction was quenched with 1M HCl (1.5 L). The aqueous layer was washed with diethyl ether (1 L) and then basified (pH=9) with 2N NaOH (1.25 L). The resulting mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate 1:1. Collected fractions after solvent evaporation afforded the title compound (D10) (15.7 g) as a grey solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:28][CH2:29]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: COCC(=O)Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)COC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f17) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[C:43]([F:46])([F:45])[F:44])(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[C:43]([F:46])([F:44])[F:45])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(F)cc1C(F)(F)F
Reaction time: 2 h
Yield: 90 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-fluoro-2-(trifluoromethyl)benzenesulfonamide (20 mg, 0.031 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-fluoro-2-(trifluoromethyl)benzenesulfonamide (percentage yield: 90%), was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[O:10])=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(I)cc4)CC3)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-c5cncnc5)cc4)CC3)c2cc1OC
Temperature: 100 °C
Yield: 35.6 %

Procedure:
To a suspension of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide (58.2 mg, 0.11 mmol), as prepared in Example 2b, in 1 mL of toluene/EtOH (4:1, v/v) were added pyrimidine-5-boronic acid (15.3 mg, 0.12 mmol), Pd(PPh3)4 (6.5 mg) and 2M K2CO3 solution (0.23 mL). The reaction mixture was heated at 100° C. overnight. It was concentrated under reduced pressure and the black residue was purified by flash column chromatography on silica gel (5% MeOH/EtOAc as eluent) to afford the desired product (18.4 mg, 35.6% yield). 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 9.09 (s, 1H), 8.94 (s, 2H), 7.55 (s, 4H), 7.38 (s, 1H), 7.27 (s, 1H), 6.59 (s, 1H), 4.32 (m, 2H), 4.09 (s, 3H), 4.08 (s, 3H), 3.65 (m, 1H), 3.23 (m, 2H), 2.19 (m, 2H), 2.03 (m, 2H). LC-MS (ESI) calcd mass 470.2, found 471.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:31]=[C:18]4[C:19]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[O-:32][CH2:33][CH3:34].[Na+]>CCO>[F:30][C:25]1[CH:24]=[C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([O:32][CH2:33][CH3:34])[CH:7]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CC[O-]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)cc1F
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)ccn1
Temperature: 150 °C
Yield: 3.3 %

Procedure:
To a solution of N-(1-(2-chloropyridin-4-yl)piperidin-4-yl)-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 169c) (88 mg, 0.20 mmol) in EtOH (1 mL) was added sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) and the reaction mixture was heated in the microwave to 150° C. for 30 minutes. Again sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) was added and the resulting mixture heated to 150° C. for another 30 minutes. The mixture was then evaporated. Purification by chromatography (silica gel, 20 g, 0 to 100% methanol in dichloromethane) afforded the title compound (3 mg, 3%) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].O.[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>O1CCCC1>[C:14]([O:13][C:11]([NH:6][C@@H:5]([CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:10])[C:3]([O:2][CH3:1])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.0 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[C:18](C)=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22]C(=O)C1C=CC(O)=CC=1OC>>[C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[C:17]([O:22][CH3:21])[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)cc1OC
Product: COc1cc(CCC(=O)OC(C)(C)C)ccc1C(=O)O

Procedure:
The title compound is prepared in analogy to 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid starting from 4-hydroxy-2-methoxy-benzoic acid methyl ester; LC-MS: tR=0.94 min, [M+1]+=281.23; 1H NMR (CDCl3): δ 1.34 (s, 9 H), 2.40-2.47 (m, 2 H), 2.76-2.85 (m, 2 H), 3.83 (s, 3 H), 7.21-7.28 (dd, J=7.6, 3.2 Hz, 1 H), 7.41-7.49 (m, 2 H).