Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]3[NH:28][N:29]=[CH:30][C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:53]([O:57][C:58]([N:60]([CH:73]([CH3:75])[CH3:74])[CH2:61][C@H:62]([C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[C:63](O)=[O:64])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:72][C:69]1[CH:70]=[CH:71][C:66]([C@H:62]([C:63](=[O:64])[N:15]2[CH2:14][CH2:13][N:12]([C:18]3[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][N:21]=[C:20]4[NH:28][N:29]=[CH:30][C:19]=34)[CH2:17][CH2:16]2)[CH2:61][N:60]([CH:73]([CH3:74])[CH3:75])[C:58](=[O:59])[O:57][C:53]([CH3:55])([CH3:54])[CH3:56])=[CH:67][CH:68]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(C(F)(F)F)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIEA (0.0607 mL, 0.349 mmol) was added to a solution of 4-(piperazin-1-yl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.030 g, 0.0872 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0336 g, 0.105 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0298 g, 0.0872 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 2 hours. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1) and an aqueous LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.027 g, 54%). MS APCI (+) m/z 495.3 detected.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(N3C(=O)c4ccccc4C3=O)n[nH]c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(O)ccc12
Temperature: 200 °C
Yield: 69 %

Procedure:
A mixture of 24.2 g (82.5 mmol) of 2-({6-methoxy}-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione and 73.4 g (0.635 mol) of piridine hydrochloride was heated at 200° C. for 4 hours. The resulting brown solution was cooled to 140° C. and slowly poured in a well stirred mixture of 250 ml of 0.2 N HCl and 350 ml of ethyl acetate. The organic layer was separated and the aqueous layer was salted (45 g of NaCl) and extracted twice with 350 ml of ethyl acetate. Organic extracts were dried over sodium sulfate and concentrated under vacuum to small volume. The precipitate was filtered off and dried: 15.89 g of product as yellow solid were obtained. Yield=68.9%. mp=265-270° C. dec.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]>O.CO.[Pd]>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
3.50 Grams of Z-Ala-Gln-OH was dissolved in 50 ml of water and 30 ml of methanol, and the mixture was catalytically reduced by using palladium as a catalyst to obtain H-Ala-Gln-OH.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=CCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCCOc1ccc(CCCCCC(=O)O)cc1
Yield: 94.2 %

Procedure:
This compound was synthesized from 6-(p-butoxyphenyl)-5-hexenoic acid (2.62 g, 10 mmol) by a hydrogenation reaction using Pd/C (260 mg). Crystallization (petroleum ether) afforded the product (2.49 g, 94%) as white crystals (mp 39-40° C.). IR: 3400=2500, 1705 cm-1 ; 1H-NMR: 0.96 (t, 3H), 1.35 (m, 2H), 1.50 (m, 2H), 1.62 (m, 4H), 1.75 (m, 2H), 2.35 (t, 2H), 2.52 (t, 2H), 3.92 (t, 2H), 6.95 (q, 4H), 10.30 (bs, 1H). Anal. Calcd. for C16H24O3 : C, 72.69, H, 9.15%; Found: C, 72.78, H, 9.18%.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:35][NH:36][O:37][CH3:38].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][N:36]([CH3:35])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: COC(C(=O)O)c1ccc(N2CCOCC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 90.7 %

Procedure:
To a suspension of 2-methoxy-2-(4-morpholinophenyl)acetic acid (2.97 g, 11.8 mmol) in anhydr. CH2Cl2 (66 mL) in an oven-dried flask under argon was added N-methylmorpholine (3 mL, 27.3 mmol) and the resulting solution was cooled over ice. Isobutylchloroformate (1.8 mL, 13.76 mmol) was added dropwise. After stirring for 50 min, N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.3 mmol) was added and the mixture was allowed to warm slowly to room temp. After stirring for 16 hours, saturated aqueous NaHCO3 was added and the mixture stirred for >15 min. The mixture was diluted with CH2Cl2 and the layers were separated. The organics were washed with brine, dried over MgSO4/Na2SO4 and concentrated. Purification by chromatography (60-85% EtOAc-hexanes) gave N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl) acetamide as an off-white solid (3.15 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:15][C:16]#[CH:17])[CH2:12][C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:18]1C=CC=C1CC(O)=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][C:13]3=[CH:14][S:18][CH:17]=[C:16]3[CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(CC#C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)Cc1cccs1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1

Procedure:
A solution of 4-methyl-N,N-diprop-2-yn-1-ylbenzenesulfonamide obtained in Step A (700 mg), thiolacetic acid (0.267 mL), and AIBN (37 mg) in benzene (90 mL) was refluxed overnight. The solvent was removed under reduced pressure, and the residue was purified on a Biotage Horizon® system (silica, gradient 30-100% dichloromethane in hexane) to yield the title compound. LC-MS 126.1 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:38])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:37])[CH2:16][CH2:17][C:18](=[O:36])[C@@H:19]([NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[C:28]([NH:27][C@@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:18](=[O:36])[CH2:17][CH2:16][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:38])=[O:8])=[O:37])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
To a stirred solution of the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline benzyl ester (100 mg, 0.1951 mmol) in dry EtOAc-MeOH (3:1 ratio) (10 mL) was added 10% Pd/C (100 mg) and the resulting mixture stirred at room temperature under 1 atmosphere of hydrogen for 24 h. Filtration of the black Pd residue and evaporation of the filtrate gave a pale yellow crude residue. Column chromatography on silica gel elution with 37% MeOH-EtOAc afforded the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline 5a as a white solid powder (68 mg, 82%): mp 148-149° C. (lit.12 mp 151-153° C.); Rf 0.28 (37% MeOH-EtOAc); IR (KBr) ν 1765 (CO), 3300 (broad, COOH) cm−1; 1H NMR (300 MHz, CD3OD) δH 2.01 (2H, m, —CH2), 2.51 (4H, m, —CH2CO and —CH2CH2N), 2.78 (2H, m, —CH2CO), 3.02-3.38 (4H, m —CH2Ph and —CH2N—), 4.84 (1H, m, —CH—), 4.98 (1H, m, —CH—) and 7.08-7.68 (10H, m, Ar—H); 13C NMR (75 MHz, CD3OD) δC 22.6, 24.5, 28.6, 34.3, 36.2, 46.4, 59.9, 61.8, 126.6 (2C), 126.8 (2C), 128.4, 128.9 (2C), 129.0, 131.6, 133.5, 136.6, 136.9, 167.9, 171.0, 179.3 and 208.9; HRMS m/z calcd for C24H26N2O5 (M+) 422.18417, found 422.18417. [± The carboxylic acid and amide protons were not observed, presumably, due to rapid exchange with water in the deuteriated NMR solvent.]
Reaction SMILES: [CH2:1]([C:8]1[C:17](C#N)=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]C1C(Cl)=NC2C(=CC=CC=2)N=1.C1C=CC2C(=NC3C(N)=NNC=3N=2)C=1.C([Mg]Cl)C1C=CC=CC=1>C1COCC1>[CH2:1]([C:8]1[C:17]([Cl:20])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: N#Cc1nc2ccccc2nc1Cc1ccccc1
Agent: Cl[Mg]Cc1ccccc1
Agent: Nc1n[nH]c2nc3ccccc3nc12
Solvent: C1CCOC1
Product: Clc1nc2ccccc2nc1Cc1ccccc1

Procedure:
Intermediate 3 can be prepared from the starting material 2,3-dichloroquinoxaline 1 following the reaction in Scheme 1. In this manner, quinoxaline 1 can be reacted with benzylmagnesium chloride in THF to afford 2-benzyl-3-chloroquinoxaline 2. 2-Benzylquinoxalines can also be prepared by reaction with alternative alkylating reagents, such as, but not limited to, benzyllithium. 2-Benzyl-3-chloroquinoxaline 2 can be reacted with cyanide to obtain intermediate 2-benzyl-3-cyanoquinoxaline 3.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][NH:20][C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][N:20]([CH3:28])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3c(=O)[nH]nc(Cl)c32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(Cl)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 50 %

Procedure:
The procedure of Example 32 was repeated except that 1-[4-(4-chlorobenzoyl)benzyl]-7-chloroimidazo[4,5-d]pyridazin-4(5H)-one was used as the starting compound. Thus, this starting compound (424 mg) was dissolved in DMF (7 ml) followed by addition of potassium carbonate (465 mg). Then, methyl iodide (0.2 ml) was added and the mixture was stirred at room temperature for 65 hours. To this reaction mixture was added water (50 ml) and the resulting crystals were harvested by filtration. This crystal crop was purified by silica gel column chromatography (stationary phase 30 g; ethyl acetate: methanol=1:0-20:1) to provide 218 mg (50%) of the title compound. 1H-NMR (CDCl3) δ: 3.87(3H,s), 5.74(2H,s), 7.23(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH2:21]CC(O)=O)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:41]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH2:21][OH:41])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CCC(=O)O)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 4-(1-phenyl-1-(5-carboxyethylpyridin-3-yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.058 g, 0.137 mmol) in dry THF (2 mL) was added LAH (0.334 mL, 0.949 mmol) portionwise over 10 min. The mixture was stirred at room temperature for an additional 30 min and then it was quenched with a saturated aqueous solution of Rochelle's salt (5 mL). The resulting mixture was filtered and the filtrate concentrated to dryness to give the title compound (0.046 g, 87%) as a clear brown oil:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(O)CCC.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: CCCCCCCCCCCCN
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCCNc1ccnc(Cl)n1
Reaction time: 40 h
Yield: 54.1 %

Procedure:
To a well-stirred slurry of 2,4-dichloropyrimidine (27.0 g, 0.18 m) and n-butanol (150 ml) is added 150 ml of water followed immediately by n-dodecylamine (67.2 g, 0.36 m). The clear solution obtained after a short time gradually clouds as the product precipitates. After allowing to stir about 40 hours, the mixture is filtered, the semi-dry cake is flushed several times with small portions of water, washed twice with water and finally sucked dry to yield 29.2 g (64%) of 2-chloro-4-(n-dodecylamino)pyrimidine, m.p. 80°-82° C.
Reaction SMILES: [C:1]([C:4]1[C:11]([Cl:12])=[C:8]([C:9]#[N:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:21])C(=O)C1>>[C:1]([C:4]1[C:11]([Cl:12])=[C:8]([C:9]#[N:10])[C:7]([NH2:13])=[C:6]([Cl:21])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1ccc(N)c(C#N)c1Cl
Product: CC(=O)c1cc(Cl)c(N)c(C#N)c1Cl

Procedure:
Using the procedure of example 42, 5-acetyl-6-chloroanthranilonitrile is chlorinated with NCS to afford 5-acetyl-3,6-dichloroanthranilonitrile, which is then converted to 3,6-dichloro-5-[2-(tert-butylamino)-1-hydroethyl]anthranilonitrile by the method of example 59.
Reaction SMILES: C([C:8]1[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(OC(C)(C)C)=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(O)(C(F)(F)F)=O>O>[NH2:18][CH2:17][C:15]1[CH:16]=[CH:8][C:9]([C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([Cl:19])=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:22]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1cc(CN)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple BOC-4-(aminomethyl)benzoic acid (48 mg) with 4-chloro-3-(pyridin-2-yl)aniline (35 mg). The crude reaction mixture was treated with TFA (1 mL) containing trace amounts of water for 1 h. The reaction mixture was concentrated to yield 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[NH4+:16]>CO>[NH2:16][C:3]([CH:2]([CH3:11])[CH3:1])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C=C(N)C(C)C

Procedure:
Ethyl 4-methyl-3-oxopentanoate (4.5 mL, 27.9 mmol) and ammonium acetate (12.05 g, 156 mmol) in MeOH (50 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo and chloroform (50 mL) was added. The resulting solid was filtered and washed with chloroform (2×25 mL). The combined filtrate was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give ethyl 3-amino-4-methylpent-2-enoate, which was carried onto the next step without further purification. MS ESI calc'd. for C8H15NO2 [M+1]+ 158. found 158.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([CH3:19])=[C:10]([I:18])[C:11](O)=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1.CI.O>CN(C)C=O>[Cl:7][C:8]1[C:9]([CH3:19])=[C:10]([I:18])[C:11]([O:4][CH3:1])=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
Potassium carbonate (72.4 g, 524 mmol) was added to a mixture of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (81.3 g, 262 mmol) and methyl iodide (19.6 mL, 314 mmol) in N,N-dimethylformamide (250 mL). The mixture was stirred at room temperature for 4 hours. Water (500 mL) was added and stirred for 15 minutes. The dark solids were filtered and dried in vacuo to give 42.3 g of the desired product. The filtrate was extracted with EtOAc (4×). The combined filtrates were washed with water (2×) and brine, dried (MgSO4), filtered and concentrated. The solids were dried in vacuo to give an additional 37.2 g of the desired product. The product was used without further purification, LCMS calculated for C10H11ClIO2 (M+H)+: m/z=324.9; Found: 325.0. 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 3.78 (s, 3H), 2.65 (s, 3H), 2.62 (s, 3H) ppm.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:24]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([Cl:29])=[CH:26][C:25]=3[Cl:30])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cc(Cl)c(N2CCNCC2)c(Cl)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3c(Cl)cc(Cl)cc3Cl)CC2)c(OC)nc1C
Yield: 54 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4,6-trichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][C:29]1[CH:28]=[C:27]([NH:26][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[C:16][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=4)[N:7]=3)=[CH:22][CH:21]=2)=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1
Reactant: CC(=O)Nc1cn2nc(I)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(C#Cc3ccc(NC(=O)Nc4cccc(C)c4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (65 mg, 0.215 mmol, 1 eq) and 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea (80.7 mg, 1.5 eq) in anhydrous DMF (2 mL) under nitrogen atmosphere was added triethylamine (0.12 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (15 mg, 0.1 eq) and copper(I) iodide (8.2 mg, 0.2 eq). After the reaction mixture was stirred at room temperature for 10 minutes, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the oily residue was wrapped with silica gel which was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:9) to give N-(6-{[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]ethynyl}imidazo[1,2-b]pyridazin-2-yl)acetamide as a brown solid in amount of 31 mg.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:35][NH2:36])=[O:34]>CN1C(=O)CCC1>[NH2:8][C:6]1[N:7]=[C:2]([NH:36][NH:35][C:33]([C:29]2[O:28][CH:32]=[CH:31][CH:30]=2)=[O:34])[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=1
Reactant: NNC(=O)c1ccco1
Reactant: Nc1nc(Cl)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Solvent: CN1CCCC1=O
Product: Nc1nc(NNC(=O)c2ccco2)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Temperature: 25 °C

Procedure:
A solution of the title A compound, 4-chloro-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl) -7H-pyrrolo[2,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol) and 2-furoic acid hydrazide (49 mg, 0.39 mmol) in 1 mL of NMP is heated at 150° C. for 3 h. After cooling to RT, the crude reaction is purified by column chromatography on silica gel, eluting with a gradient of 5% to 10% of MeOH in EtOAc. Fractions containing the product are combined and evaporated to dryness to afford N′-(2-amino-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide yellow solid: LC/MS (M+1=483.2).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Yield: 75 %

Procedure:
Solid (2R)-1-(3'-(Benzyloxy)biphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.88 g, Example 93c) was dissolved in dry ethanol (150 ml) and hydrogenolysed for 24 hours at 3 atmospheres pressure over a palladium on carbon catalyst (10%, 0.09 g). The reaction mixture was filtered through Celite® and the residue washed with ethanol. The combined filtrate and washings were concentrated under reduced pressure and the residue obtained purified by column chromatography over silica eluting with dichloromethane:methanol (98:2) to give the title compound as a white solid (0.52 g).