Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14](O)[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)C2CCCCC21
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC2CCCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one (2.1 g), dicyclohexylcarbodiimide (1.8 g) and cuprous chloride (0.2 g) is heated at 80° under nitrogen for 32 hours. The reaction mixture is cooled to room temperature, the residue is dissolved in methylene chloride (200 ml), washed with dilute ammonium hydroxide (2×50 ml) and water (50 ml). The organic phase is dried over sodium sulfate and evaporated to give a mixture of the desired adduct and excess dicyclohexylcarbodiimide. This mixture is dissolved in ethyl acetate (100 ml) and placed in a pressure bottle. 10% Pd/C (0.4 g) is added and the mixture hydrogenated at 3 atmospheres pressure and 40° for 16 hours. The catalyst is filtered off and the filtrate is evaporated to give 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one, used without further purification for the next synthetic step.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)c1c(C)cc(I)cc1C
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2cc(C)c(C(C)=O)c(C)c2)cc1
Yield: 89.1 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4-methoxybenzenethiol (1.01 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.41 g, 4.9 mmol) as yellow oil in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.39 (d, J=8.5 Hz, 2 H), 6.96 (d, J=8.5 Hz, 2 H), 6.79 (s, 2 H), 3.82 (s, 3 H), 2.43 (s, 3 H), 2.13 (s, 6 H); ESI-MS: m/z 287.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([N:6]([CH2:10][CH:11]1[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH3:9])=[O:5].[CH2:18]([NH:21][CH2:22][CH:23]1CC1)[CH2:19]C.C12C(=CC=CC=1)[NH:31]C(=O)OC2=O>>[CH:11]1([CH2:10][N:6]([CH2:7][CH2:8][CH3:9])[C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[NH:1][CH2:23][C:22]2[NH:31][CH2:19][CH2:18][N:21]=2)[CH2:12][CH2:13]1
Reactant: CCCNCC1CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCN(CC1CC1)C(=O)c1ccccc1N
Product: CCCN(CC1CC1)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-(cyclopropylmethyl)-N-propylbenzamide (prepared from N-propylcyclopropanemethylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-(cyclopropylmethyl)-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-propylbenzamide.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:25])(=O)=O)C=CC=CC=1.O.Cl>C(O)C.C(COC)OC>[CH3:25][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[C:16]([C:21]([F:23])([F:22])[F:24])[CH:17]=[CH:18][CH:19]=2
Reactant: Cc1cc2c(C(F)(F)F)cccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Yield: 79.3 %

Procedure:
0.271 ml of 5N sodium hydroxide is added to a solution of 460 mg of 1-benzenesulfonyl-2-methyl-4-trifluoromethyl-1H-indole in 1.4 ml of ethanol and 0.44 ml of dimethoxyethane. The reaction mixture is maintained at reflux for 6 hours and poured into water acidified with a hydrochloric acid solution until pH=1 and extracted with ethyl acetate. The organic phases are combined and washed with a 10% sodium bicarbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 214 mg of 2-methyl-4-trifluoromethyl-1H-indole, in the form of a pale yellow oil, which is used in the next step.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>C(OC(=O)C)(=O)C>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:1]([O-:3])=[O:2])=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CCCc2ccccc2O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CCCc2cc([N+](=O)[O-])ccc2O)cc1
Product: COC(=O)c1ccc(CCCc2cccc([N+](=O)[O-])c2O)cc1
Reaction time: 0.25 h

Procedure:
Nitric acid (15M, 3.13 ml) was added to acetic anhydride 12.52 ml) at 0° C. and the mixture stirred for 15 minutes, then added to a stirred solution of methyl 4-[3-(2-hydroxyphenyl)-propyl]benzoate (12.89 g) in acetic anhydride (300 ml) at 0° C. and stirred for 18 hours. The solvent was evaporated and the resulting yellow oil purified by chromatography on silica gel using ethyl acetate: hexane (1:9 to 1:1 gradient) as eluant to give methyl 4-[3-(2-hydroxy-3-nitrophenyl)propyl]benzoate (5.4 g) and methyl 4-[3-(2-hydroxy-5-nitrophenyl)propyl]benzoate (7.5 g).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH3:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:20]([CH3:27])[CH:21]=1)#[N:24]
Reactant: Cc1cc(C#N)ccc1CO
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixture of methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6, 112 mg, 0.51 mmol), 4-(hydroxymethyl)-3-methylbenzonitrile (83 mg, 0.56 mmol), PPh3 (268 mg, 1.02 mmol) and THF (6 mL) cooled in ice-water bath, DIAD (207 mg, 1.02 mmol) was added. The mixture was stirred overnight at room temperature. It was then concentrated and purified by flash column chromatograph to give 112 mg of the title compound (63%). [M+H] Calc'd for C19H16N4O3, 349. Found, 349.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C[CH:17]([CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23])[C:18](O)=[O:19].[CH2:29](Cl)CCl>ClCCl>[CH3:29][O:24][C:22](=[O:23])[CH:21]([CH2:17][C:18]([N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)=[O:19])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CC(C(=O)O)C(C)C(=O)O
Reactant: ClCCCl
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Solvent: ClCCl
Product: COC(=O)C(CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1)CC(C)C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
4-(4-Chlorobenzoyl)piperidine (0.2 g) was added to a solution of methyl 3-isobutylsuccinic acid (0.15 g) and EDC (0.25 g) in dichloromethane (10 ml) and the solution was stirred for 18 h, then washed with water (10 ml), aqueous citric acid (10 ml), saturated sodium bicarbonate (10 ml) and brine (10 ml), dried over magnesium sulphate (1 g) and evaporated to give the title compound (0.25 g) as a colourless solid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Agent: Cl
Product: O=C(/C=C/c1ccc(Br)cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-bromophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 335, 337 (MH+H).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]([NH:12][C@@H:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:14]([O:16]C)=O)=[O:11])[CH3:6].[Na]>C(O)C>[OH:16][C:14]1[C@H:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:12][C:10](=[O:11])[C:9]=1[C:8]([O:7][CH2:5][CH3:6])=[O:22]
Reactant: CCOC(=O)CC(=O)N[C@@H](CC(C)C)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(O)[C@H](CC(C)C)NC1=O
Temperature: 25 °C

Procedure:
A solution of 123.1 g (0.38 mol, 2.5% less than theory) of "21 weight percent sodium ethoxide in ethanol" (Aldrich Chemical Co.) is added all at once to a solution of 101 g (0.39 mol) of (S)-2-[(3-ethoxy-1,3-dioxopropyl)amino]-4-methylpentanoic acid, methyl ester in 200 ml of absolute ethanol. There is no heat of reaction. After about two minutes a solid separates (sodium salt of product) and the mixture becomes thick. The mixture is heated at reflux for 30 minutes (complete solution) and then cooled to room temperature (solid reappears). The solid is collected by filtration and washed with diethyl ether. The resulting cake is dissolved by adding to 1 L of ice water with stirring, 400 ml of 1N hydrochloric acid solution is added and the separated solid is filtered, washed with water and dried one hour under suction to afford (S)-2,5-dihydro-4-hydroxy-5-(2-methylpropyl)-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester as a moist solid which is used in the next steps without further purification. TLC (acetic acid, methanol, chloroform, silica gel, iodine) Rf =0.6.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3].[CH:10]([OH:13])([CH3:12])[CH3:11]>O1CCOCC1>[CH:10]([O:13][C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3])([CH3:12])[CH3:11]
Reactant: CC(C)O
Reactant: O=C(Cl)N1CCNC1=O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N1CCNC1=O

Procedure:
14.9 parts by weight of N-chlorocarbonylimidazolid-2-one in 100 parts by volume of i-propanol and 100 parts by volume of dioxane were warmed to 50° C for 3 hours. After stripping off the solvent, the residue was recrystallized from acetone.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N+](C1C=CC(O[C:36](=[O:44])[O:37][CH2:38][C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[O:41]1[CH:42]=[CH:43][C:39]([CH2:38][O:37][C:36](=[O:44])[N:2]([CH3:1])[CH:3]2[CH2:16][C:15]3[C:6]([CH3:25])([CH:7]4[CH:12]([CH2:13][CH:14]=3)[CH:11]3[CH2:17][CH2:18][CH:19]5[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]35[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)=[CH:40]1
Reactant: O=C(OCc1ccoc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCc6ccoc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
Compound 7B (10 mg, 0.029 mmol), carbonic acid furan-3-ylmethyl ester 4-nitro-phenyl ester (2.4 mg, 0.032 mmol) and triethylamine (12.0 μL, 0.087 mmol) were dissolved in THF (1 mL) and stirred at room temperature overnight. The crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (10.1 mg, 74.2% yield).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:3]=1.Cl.[CH3:26][C:27]1[N:28]=[C:29]([NH:32][C:33]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]2)=[O:34])[S:30][CH:31]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:38]4[CH2:39][CH2:40][CH2:41][C@@H:36]([NH:35][C:33]([NH:32][C:29]5[S:30][CH:31]=[C:27]([CH3:26])[N:28]=5)=[O:34])[CH2:37]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: Cc1csc(NC(=O)N[C@@H]2CCCNC2)n1
Reactant: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)N[C@@H]2CCCN(c3ccc(C(N)=O)c(Nc4ccc(N5CCN(C)CC5)cc4)n3)C2)n1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
A mixture of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide (60 mg, 0.173 mmol), (R)-1-(4-methylthiazol-2-yl)-3-(piperidin-3-yl)urea hydrochloride (96 mg, 0.347 mmol), and DIEA (0.182 mL, 1.041 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 120° C. overnight. The reaction mixture was quenched with water, resulting in the formation of light brown precipitate. The solid was filtered, washed with water, and dried under vacuum. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 22 mg of (R)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-6-(3-(3-(4-methylthiazol-2-yl)ureido)piperidin-1-yl)nicotinamide as a yellow solid. LCMS: (M+H)+=550.08; 1H NMR (400 MHz, CDCl3) δ ppm 10.62 (1H, s), 7.47 (2H, d, J=9.23 Hz), 7.33 (1H, d, J=8.79 Hz), 6.85 (2H, d, J=9.23 Hz), 6.28 (1H, s), 5.91 (1H, d, J=8.79 Hz), 5.69 (2H, br. s.), 4.00 (1H, d, J=7.47 Hz), 3.65-3.79 (2H, m), 3.55-3.64 (1H, m), 3.40-3.50 (1H, m), 3.07-3.14 (4H, m), 2.52-2.58 (4H, m), 2.33 (3H, s), 2.19 (3H, s), 1.87-1.98 (1H, m), 1.55-1.82 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:15][C:16]([NH:18][CH2:19][CH2:20]C1C2C=C(OC)C=CC=2NC=1)=[O:17]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:20][CH2:19][NH:18][C:16](=[O:17])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Nc2ccccc2)c1
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Solvent: C1CCOC1
Product: CC(=O)NCCN(c1ccccc1)c1cccc(Br)c1

Procedure:
A solution of nitrile 4f (1.16 mmol), prepared according to the method previously described for the preparation of 4a, but starting with N-(3-bromophenyl)-aniline (3f) [yield (4f): 37%; oil; 1H-NMR (CDCl3): δ 4.50 (s, 2H), 6.87 (m, 1H), 7.08-7.46 (m, 8H)] in dry THF (6 mL), was hydrogenated according to the procedure previously described for the preparation of 5a to provide the title compound 5f. The crude product was purified by flash-chromatography on silica gel (dichloromethane/acetone, 95:5 as eluent). Yield (5f): 20%; 1H-NMR (CDCl3): δ 1.90 (s, 3H), 3.48 (m, 2H), 3.85 (m, 2H), 6.03 (brs, 1H), 6.81-7.41 (m, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)=O.[CH2:27]([OH:32])[C:28](F)(F)F.ClC(Cl)(Cl)C(=N)OC.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42]>>[CH2:41]([N:43]([CH2:44][CH3:45])[C:27]([C:28]1[NH:10][C:9]2=[N:8][C:7]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])[CH2:12]3)=[CH:6][CH:5]=[C:4]2[N:3]=1)=[O:32])[CH3:42]
Reactant: OCC(F)(F)F
Reactant: CCNCC
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: COC(=N)C(Cl)(Cl)Cl
Agent: Cl
Solvent: O=CO
Product: CCN(CC)C(=O)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.22 h

Procedure:
Into a vial containing (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (125 mg, 0.3 mmol) was added formic acid (73.5 μL, 1.7 mmol) followed by 2,2,-trifluoroethanol (1.7 mL) and methyl 2,2,2-trichloroacetimidate (47.0 μL, 0.4 mmol). The vial was sealed and stirred at room temperature for 13 min. The reaction mixture was heated to 60° C. and stirred for 3 h at that temperature. An aliquot of 0.3 mL was transferred into another vial containing diethylamine (89.1 μL, 0.9 mmol). The resulting mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The aqueous was further extracted with ethyl acetate. The combined organics were concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 399.1; HPLC retention time 1.9864 min (Method A).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O[CH:10]1[CH2:15][NH:14][CH2:13][CH2:12][CH2:11]1.[OH2:16]>CS(C)=O>[Cl:8][C:7]1[C:2]([N:14]2[CH2:13][CH2:12][CH:11]([OH:16])[CH2:10][CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCCNC1
Reactant: Clc1cccnc1Cl
Reactant: O
Solvent: CS(C)=O
Product: OC1CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
2,3-dichloropyridine (10 g, 68 mmol) and 5-hydroxyl piperidine (compound 19) (26 g, 272 mmol) in DMSO was heated at 120° C. and stirred overnight. After the reaction was completed, three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product. (17 g, 93%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4](SC)[N:3]=1.[CH:15]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:26][S:27]([O-:29])=O.[Na+].[Na+].CC(OC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)=[CH:6][N:5]=[C:4]([S:27]([CH3:15])(=[O:29])=[O:26])[N:3]=1
Reactant: O=S([O-])[O-]
Reactant: CSc1ncc(OCC2CC2)c(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To the title compound of step 3 (19.0 g, 82.60 mmol) in dry CH2Cl2 (200 mL) at 0° C., m-CPBA (42.62 g, 247.80 mmol) was added over 15 min. The mixture was stirred at 0° C. for 30 min and at r.t. overnight. Sat.aq. Na2SO3 (100 mL) was added and CH2Cl2 extractive work up was carried out. Trituration with MTBE (300 mL) gave the title compound (17 g, 78.3% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 4.13 (d, J=6.8 Hz, 2H), 3.33 (s, 3H), 1.39-1.35 (m, 1H), 0.79-0.74 (m, 2H), 0.49-0.45 (m, 2H). LCMS: 263.0 (M+1)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)=[CH:37][CH:38]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 89 %

Procedure:
To a nitrogen de-gassed solution of methyl 2-(2-ethynylphenyl)acetate (14: prepared according to the procedure of Peng, C. et al; Adv. Synth. Catal. 2008, 350, 2359-2364 or as detailed below) (0.114 g, 0.653 mmol) in dry DMF (6 mL) were added triethylamine (0.280 mL, 2.01 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.230 g, 0.502 mmol), triphenylphosphine (0.020 g, 0.075 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.035 g, 0.050 mmol) and CuI (0.014 g, 0.075 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-80% EtOAc in cyclohexane) to give the title compound (I5) (0.267 g, 89% yield) as an orange glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.27 (br s, 1H), 8.76 (s, 1H), 7.65-7.49 (m, 4H), 7.49-7.38 (m, 2H), 6.95 (d, J=9.1 Hz, 2H), 3.94 (s, 2H), 3.61 (s, 3H), 3.51-3.42 (m, 4H), 3.09-3.00 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.67 min; m/z 596.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of 3-(benzyloxy)aniline (5.00 g) in DMF (50% mL) were added sodium acetate (2.10 g) and ethyl bromoacetate (4.20 g), and the mixture was stirred at room temperature for 12 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.80 g) as orange crystals.
Reaction SMILES: FC(S([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])(=O)=O)(F)F.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:19]([O:18][C:13](=[O:17])[C:14]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:16])[CH3:20]
Reactant: CCOC(=O)C(C)=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(O[Si](C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of trimethylsilyl trifluoromethylsulfonate (9.52 mL, 52.5 mmol) in anhydrous methylene chloride (10 mL) was added to a stirred ice-cooled solution of ethyl pyruvate (5.56 mL, 50 mmol) and diisopropylethyl amine (9.6 mL, 55 mmol) in anhydrous methylene chloride (100 mL) over a period of 15 minutes. The reaction was stirred on ice for 1.5 hours and then at room temperature for 3 hours. The solvent was evaporated at room temperature and the residue treated with anhydrous pentane (200 mL) and cooled in ice. The precipitated solid was filtered off. The filtrate was collected and the pentane evaporated to give 2-trimethylsilanyloxyacrylic acid ethyl ester as a light brown liquid (90% yield). The crude product was used for the next reaction without further purification.