Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:9][CH:10]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])[CH2:18][C:17]2[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=2[CH2:15]1)=[O:12])(=O)C1C=CC=CC=1.Cl>CO>[SH:9][CH:10]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])[CH2:18][C:17]2[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=2[CH2:15]1)=[O:12]
Reactant: CC(C)CC(C(=O)O)N1Cc2ccccc2CC(NC(=O)C(Cc2ccccc2)SC(=O)c2ccccc2)C1=O
Agent: Cl
Solvent: CO
Product: CC(C)CC(C(=O)O)N1Cc2ccccc2CC(NC(=O)C(S)Cc2ccccc2)C1=O
Yield: 80.7 %

Procedure:
Dissolve 2-[4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-4-methyl-valeric acid (0.229 mmol) in degassed methanol (3 mL) and cool in an ice bath. Treat with degassed 1N aqueous lithium hydroxide (1.0 mL) and stir, allowing the ice bath to warm gradually over 3 hours. With the reaction at 0° C., acidify with 5% hydrochloric acid. Partition between methylene chloride (75 mL) and water (25 mL), dry (Na2SO4) and purify by silica gel chromatography (3:1:0.01 hexane/ethyl acetate/acetic acid followed by 1:1:0.01 hexane/ethyl acetate/acetic acid to give the title compound as a white solid (84 mg, 80.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:18])[N:10](C(OC(C)(C)C)=O)[C:3]=12.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:20]=[O:21]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:22]([NH:19][C:20]([N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]2[NH:10][C:9]1=[O:18])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCN=C=O
Reactant: Cc1ccnc2[nH]c(=O)n(C(=O)OC(C)(C)C)c12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCNC(=O)n1c(=O)[nH]c2c(C)ccnc21

Procedure:
Analogously to Example 1, tert-butyl 7-methyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (300 mg, 1.2 mmol), 1-isocyanatohexane (183.8 mg, 1.44 mmol) and 4-dimethylaminopyridine (14.7 mg, 0.12 mmol) were reacted in toluene. Yield: 8 mg (2%), M+H+: 277.16.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>CCOCC>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[S:21]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:22])=[O:23]
Reactant: Cc1cc(O)cc(O)c1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(O)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
To a solution of 1.00 g (8.05 mmol) of orcinol monohydrate and 1.75 g (7.38 mmol) of 2,5-dimethoxybenzenesulfonyl chloride in 20 mL of diethyf ether was added 20 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to give an amber-colored solid. Recrystallization from ethyl acetate-hexane afforded 1.29 g (54%) of the title compound as a cream-colored powder: 1H-NMR (300 MHz; CDCl3) δ 7.34 (d, 1 H, J=3.1 Hz), 7.15 (dd, 1 H, J=9.1, 3.1 Hz), 7.02 (d, 1 H, J=9.1 Hz), 6.53 (m, 2 H), 6.42 (t, 1H, J=2.2 Hz), 5.08 (br s, 1 H),3.95 (s,3 H), 3.76 (s, 3 H), and 2.23 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:22]([CH3:21])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cccc(C)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(CN(C)c2cncc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1

Procedure:
A mixture of 6′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-1a (50 mg, 0.17 mmol), methyl-(6-methyl-pyridin-2-ylmethyl)-amine (29.6 mg, 0.22 mmol), sodium tert-butoxide (45 mg, 0.46 mmol), BINAP (8.4 mg, 0.014 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.2 mg, 0.006 mmol) in toluene (2 mL) was stirred at reflux for 2 h. The reaction mixture was cooled, diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified via preparative TLC (5% methanol in methylene chloride) to yield the title compound I-4g (14.2 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12].[OH-].[Na+]>O>[CH2:10]([NH:13][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=1)[CH2:11][NH:12][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=1
Reactant: NCCN
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(N)nc(NCCNc2nc(N)nc(N)n2)n1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
29.1 g of 2,4-diamino-6-chloro-s-triazine was added to 300 ml of water to obtain a slurry. Then 6 g of ethylenediamine was added thereto, and the mixture was stirred for 15 minutes. Then, 16 g of a 25 wt% sodium hydroxide aqueous solution was added thereto, and the mixture was refluxed under heating for two hours. At that time, about 3 g of a 25 wt% sodium hydroxide aqueous solution was further gradually added over a period of two hours to maintain the reaction solution in a weakly alkaline state. After completion of the reaction, the reaction mixture was left to cool, whereupon the crystals were collected by filtration and washed with water to obtain 25.3 g of ethylenebismelamine. Then, 5.9 g of ethylenebismelamine and 17 g of formaline were mixed, and mixture was subjected to a heating reaction at 90° C. for 4 hours while maintaining the mixture at pH 9 to 10 with an aqueous sodium hydroxide solution. Then, the formed methylol product was taken out, and 30 ml of methanol was added thereto. The mixture was adjusted to pH 4 with hydrochloric acid. After the solution became uniform, it was heated for 5 minutes and neutralized. Then, methanol was distilled off to obtain 3.2 g of methoxymethylated ethylenebismelamine. The product was analyzed by IR and NMR and was found to be a mixture containing octamethoxymethylethylenebismelamine as the main component.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cncc(Br)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a stirred solution of 1-(5-bromopyridin-3-yl)ethanone (5.0 g, 25.0 mmol) in anhydrous MeOH (50 mL) at 0° C., was added NaBH4 (1.32 g, 35.0 mmol) and the reaction was allowed to warm to room temperature. All solvent was removed. The residue was dissolved in cold water and extracted with EtOAc (2×70 mL). The combined organic layers was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (40% EtOAc in hexanes) to provide 4.555 g of 1-(5-bromopyridin-3-yl)ethanol.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([O:16][CH3:17])[C:4]([CH2:1][CH3:2])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(C)=O)c(OC)cc1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)OC)c(OC)cc1OC
Reaction time: 0.33 h

Procedure:
A 0.50 g portion of methyl 5-acetyl-2,4-dimethoxybenzoate was dissolved in 10 ml of trifluoroacetic acid, 0.83 ml of triethylsilane was added, followed by 20 minutes stirring. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 0.50 g of methyl 2,4-dimethoxy-5-ethylbenzoate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14]O)[C:8](=[O:16])[C:7](=[O:17])[NH:6]2.S(Cl)([Cl:22])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][Cl:22])[C:8](=[O:16])[C:7](=[O:17])[NH:6]2
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCO)c1=O
Reactant: O=S(Cl)Cl
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCCl)c1=O

Procedure:
1.3 g (4.7 mmol) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl alcohol is stirred in 20 ml of thionyl chloride for 4 hours at room temperature. After concentration by evaporation and subsequent distillation with toluene, 1.34 g (97% of theory) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl chloride is obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[CH:10]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:27]1([C:25]([N:22]([CH2:21][C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=2[C:9]2[CH:10]=[C:5]([CH2:4][C:3]([OH:30])=[O:2])[CH:6]=[N:7][CH:8]=2)[CH2:23][CH3:24])=[O:26])[CH2:29][CH2:28]1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester (0.069 g, 0.16 mmol) was dissolved in THF (1 mL) and MeOH (0.8 mL) and treated with 1N aqueous NaOH (0.5 mL). The reaction was stirred at room temperature for 1 hour. The mixture was neutralized with 1N aqueous HCl and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give Compound 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[CH:6]=1.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:6]=1
Reactant: CC(C)(C(=O)O)n1cc(Br)cn1
Reactant: CC(C)CN
Product: CC(C)CNC(=O)C(C)(C)n1cc(Br)cn1
Yield: 95 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid and isobutylamine. Yield: 95%. 1H NMR (400 MHz, CDCl3): δ 0.81 (d, 3H, J=6.8 Hz), 1.63-1.67 (m, 1H), 1.84 (s, 6H), 2.99 (t, 2H, J=6.8 Hz), 6.19 (br, 1H), 7.61 (s, 1H), 7.64 (s, 1H). MS(MH+) 288, 290.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N+:31]([O-])=O)[CH:22]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:31][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:34]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:36]=[C:4]([NH2:1])[CH:5]=3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2ccc(-c3ccc(Oc4cc([N+](=O)[O-])cc(C(F)(F)F)c4)cc3)cc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cc(Oc2ccc(-c3ccc(Oc4cc(N)cc(C(F)(F)F)c4)cc3)cc2)cc(C(F)(F)F)c1
Yield: 96 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 33 g (0.0585 mol) of 4,4'-bis(3-nitro-5-trifluoromethylphenoxy)biphenyl, 100 ml of methyl cellosolve and 1.7 g of 5%-Pd/c having a moisture content of 50% were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered off. The filtrate was concentrated under reduced pressure to obtain 4,4'-bis(3-amino-5-trifluoromethylphenoxy)biphenyl as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[N:11](C2CCCCO2)[N:10]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(C2CCCCO2)c2ccc(C#N)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1n[nH]c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(2-Methoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.539 g, 2.17 mmol) was dissolved in 10 mL of tetrahydrofuran. Aqueous hydrogen chloride (10 mL, 6.0N) was added and the reaction mixture was stirred at room temperature for 12 hours, then reflux temperature for 7 hours. The pH of the reaction was neutralized using saturated sodium bicarbonate and the crude was extracted with ethyl acetate (3×15 mL). Attempt to purify the crude by column chromatography was unsuccessful: ES-MS (m/z) 250 [M+1]+.
Reaction SMILES: COC(C1CCCN1C(C1N2C(COCC2)=C(C(=O)N[C@@H](C2C=CC=CC=2)CC)C=1)=O)=O.[CH:33]([O:36][C:37]([CH:39]1[CH2:43]C[CH2:41][N:40]1[C:44]([C:46]1[N:54]2[C:49]([CH2:50][O:51][CH2:52][CH2:53]2)=[C:48]([C:55](=[O:66])[NH:56][C@@H:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:58][CH3:59])[CH:47]=1)=[O:45])=[O:38])(C)[CH3:34].C(O)(C)C>C(O)C>[CH2:33]([O:36][C:37](=[O:38])[C@@H:39]([N:40]([CH3:41])[C:44]([C:46]1[N:54]2[C:49]([CH2:50][O:51][CH2:52][CH2:53]2)=[C:48]([C:55](=[O:66])[NH:56][C@@H:57]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:58][CH3:59])[CH:47]=1)=[O:45])[CH3:43])[CH3:34]
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCCC2C(=O)OC(C)C)n2c1COCC2)c1ccccc1
Agent: CC[C@@H](NC(=O)c1cc(C(=O)N2CCCC2C(=O)OC)n2c1COCC2)c1ccccc1
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)[C@H](C)N(C)C(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)c2n1CCOC2

Procedure:
The compound was obtained from comp. no. 16m as starting compound in analogy to the synthesis of comp. no. 16n. Isopropanol was replaced by ethanol to form the ester. LC/MS (method 4): Rt=1.24 min; m/z=454.27 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11].C([O-])(=O)C.[Na+].[ClH:17]>[Pd].[Pt]=O.C(O)(=O)C>[ClH:17].[NH2:11][CH2:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Agent: O=[Pt]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(CN)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Palladium on carbon (10%) (3.24 g) was charged into a 2 L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (30 g, 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L). The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H2 (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with 150 mL of conc. HCl, and the formed solids were filtered. The yellow filtrate was concentrated. To the crude compound was added 30 mL of conc. HCl and 150 mL EtOH, the contents cooled to 0° C., and stirred at 0° C. for 2 h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (br s, 1H) 8.13 (br s, 3H) 5.93-6.01 (m, 1H) 3.72-3.80 (m, 2H) 2.22 (s, 3H) 2.16 (s, 3H).
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][NH2:13])=[N:10][CH:11]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:13][NH:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
EDC (543 mg, 2.83 mmol) was added portionwise to a stirred solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (Aldrich, 649 mg, 2.83 mmol) and HOBt (32 mg, 0.24 mmol) in dry DCM (20 mL). The mixture was stirred at RT for 18 h. The solution was washed with water (2×20 mL), dried (Na2SO4) and evaporated. The residue was triturated (diethyl ether) to give the title compound as an off-white solid (713 mg, 82%). LCMS (Method 1): Rt 2.76 min, m/z 339 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (60) (40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[NH:7][C:6]1([CH3:14])[CH3:13].[Cl:15]OC(C)(C)C>CO>[Cl:15][N:7]1[C:8]([CH3:12])([CH3:11])[C:9](=[O:10])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1([CH3:14])[CH3:13]
Reactant: COCCN1C(=O)C(C)(C)NC1(C)C
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
A solution of 3-(2-methoxyethyl)-2,2,5,5-tetramethylimidazolidin-4-one (0.70 g, 3.5 mmol) in methanol (10 mL) was cooled in ice water for 10 minutes, before neat tert-butyl hypochlorite (0.59 mL, 5.25 mmol, 1.5 equiv.) was added in one portion. High pressure liquid chromatography-mass spectroscopy analysis after 5 minutes showed all starting amine had been consumed. After 20 minutes, the mixture was concentrated in vacuo to an oil. The oil absorbed was on silica (2.5 g) and was purified by silica gel flash chromatography (0-4% methanol in dichloromethane) afforded the N-chloro-imidazolidin-4-one as a colorless oil (0.78 g, 95%). 1H NMR (400 MHz, CDCl3) δ 3.55 (t, J=5.8 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 3.36 (s, 3H), 1.46 (s, 6H), 1.36 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.8, 82.0, 70.1, 65.3, 58.8, 40.5, 25.1, 23.5; LRMS (ESI/APCI) m/z 235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.O.CCOC(C)=O.[CH3:44][N:45](C=O)C>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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[C:5]2[C:10]([C:44]#[N:45])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 4-((2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (360 mg, 0.557 mmol), Pd2 dba3 (50 mg, 0.055 mmol) and dppf (62 mg, 0.11 mmol) in DMF (5 mL) was degassed with Ar before being charged with Zn(CN)2 (80 mg, 0.68 mmol). The mixture was stirred at 70° C. for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a flash silica gel column, eluted with EtOAc/hexane (0-35%) to give tert-butyl 4-((2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (127 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][C:12]=1[C:13](OC)=[O:14].[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[C:47]([NH2:48])=[CH:46][CH:45]=[CH:44][N:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[CH:17][C:12]=1[C:13]([NH:48][C:47]1[C:42]([F:41])=[N:43][CH:44]=[CH:45][CH:46]=1)=[O:14]
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1F
Reactant: Nc1cccnc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1F)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-([(2,4-difluorophenyl)methyl]oxy}-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described in Description 110, 100 mg, 0.26 mmol) in tetrahydrofuran (THF) (4 ml) was added lithium hydroxide (26 mg, 1.09 mmol) and water (1 ml). The mixture was heated at 50° C. for one hour, cooled and 2M hydrochloric acid (0.54 ml, 1.09 mmol) was added. The solvent removed in vacuo and the residue was redissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.09 ml, 0.51 mmol), 2-fluoro-3-pyridinamine (34.4 mg, 0.31 mmol) and HATU (243 mg, 0.64 mmol) were added and the mixture stirred overnight. The solvent was removed in vacuo and the residue purified by column chromatography (silicon, 10% methanol/dichloromethane) to give an oil. Purification by MDAP yielded the title compound as an off-white solid. 22 mg.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.[C:9]1([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[C:16]([OH:17])[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:21]([OH:22])[N:3]2[N:4]=1)[CH3:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CCc1nc(N)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CCc1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 0.5 h

Procedure:
A solution of 5.00 g 3-amino-5-ethyl-1,2,4-triazole and 15.00 g diethyl phenylmalonate in 18 ml N,N-dibutylbutan-1-amine is stirred at 185° C. over night. The solution is diluted with 5N NaOH solution, the resulting mixture is stirred for 30 min. The aqueous layer is washed with diethylether, acidified at 0° C. with concentrated HCl until precipition of the product is complete. The precipitate is collected by filtration to yield the product, which is used without further purification.