Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Na].[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Na]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4-chloro-3-nitrobenzotrifluoride (112.8 g) in methanol (200 ml) was mixed with a solution of sodium (11.6 g) in methanol (800 ml) and stirred for 2 hours. The mixture was kept overnight and then stirred and heated under reflux for 3 hours. The solution was left overnight, filtered, and the solvent removed. The remaining oil was taken up in ether (500 ml) and washed with water. The ether solution was dried and evaporated to give 4-methoxy-3-nitrobenzotrifluoride (106 g).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][CH3:30]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][N:13]([CH2:28][CH2:29][CH3:30])[CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CCNCCc2c[nH]cn2)c1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1cccc(OC)c1)CCc1c[nH]cn1
Yield: 31.1 %

Procedure:
A stirred mixture of 3.2 g of the product of Step B, 5.1 g of potassium carbonate, 3.4 g of 1-iodopropane and 64 ml of acetone was refluxed under an inert atmosphere for 19 hours and the acetone was evaporated. 100 ml of water and 2 ml of sodium hydroxide were added to the mixture which was then extracted 3 times with 50 ml of methylene chloride. The combined organic phases were washed with 100 ml of water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the 3.6 g of oil residue were chromatographed over silica gel to obtain 900 mg of N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-1H-imidazol-4-ethanamine in the form of a yellow oil which was used as is for the next step. C.C.M. over silica (7-3 CHCl3 -Methanol): Rf=0.20.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]([CH2:10][CH2:11][O:12][CH2:13][CH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N+:26]([O-])=O)[CH:19]=[CH:18][CH:17]=1)[OH:15])[CH3:9].CO.[OH-].[Na+].[ClH:33].C(O)C>C(O)C.[C].[Pd].C(Cl)(Cl)Cl>[ClH:33].[ClH:33].[NH2:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([CH:14]([OH:15])[CH2:13][O:12][CH2:11][CH2:10][N:8]([CH3:7])[CH3:9])=[CH:17][CH:18]=[CH:19]2
Reactant: CN(C)CCOCC(O)c1cccc2cccc([N+](=O)[O-])c12
Agent: [Pd]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CN(C)CCOCC(O)c1cccc2cccc(N)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 150 mg of 2-[2-(N,N-dimethyl-amino)ethoxy]-1-(8-nitro-1-naphthyl)ethanol oxalate, 150 mg of 5% palladium-carbon and 3 ml of methanol was subjected to hydrogenation at room temperature for 30 minutes under atmospheric pressure. After the completion of the reaction, the palladium-carbon was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue thus obtained was added to a mixture of 30 ml of ice water and 30 ml of chloroform. The mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 1 ml of ethanol. Thereto was added 0.2 ml of a 5.9N dry hydrogen chloride-ethanol solution. The resulting crystals were collected by filtration and dried to obtain 110 mg of 1-(8-amino-1-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol dihydrochloride (compound No. 290).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:14]O>>[CH3:14][O:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:13]
Reactant: CO
Reactant: O=C(O)c1nccc2ccccc12
Product: COC(=O)c1nccc2ccccc12
Yield: 50 %

Procedure:
A mixture of 1-isoquinolinecarboxylic acid (25 g.0.14 mol), 25 g of AMBERLYST®-15 (H+), and 300 ml of methanol was refluxed for 3 days. The reaction mixture was cooled, filtered, and the filtrate was concentrated in vacuo to afford 13.6 g (50%) of 1-isoquinolinecarboxylic acid methyl ester.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C[O-].[Na+].CN([CH:11]=[C:12]1[C:18](=O)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([C:24](=[O:34])[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:14][CH2:13]1)C>CO>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]([N:15]2[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]3[N:3]=[CH:2][N:4]=[CH:11][C:12]=3[CH2:13][CH2:14]2)=[O:34])=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: N=CN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cncnc2-c2ccccc21
Reaction time: 0.08 h
Yield: 107.7 %

Procedure:
To a solution of 0.152 g (1.89 mmol) of formamidine hydrochloride in 10 ml of methanol under argon is added 0.102 g (1.89 mmol) of sodium methoxide. After stirring 5 min., a solution of 0.46 g (1.26 mmol) of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepine-5-one in 5 ml of methanol is added and the mixture stirred 18 hours. The solvent is removed, dichloromethane added, and the mixture filtered. The solid is washed with dichloromethane. The combined filtrate is concentrated to dryness to give 0.47 g of tan foam. The preceding solid is purified by chromatography on silica gel. The compound is dissolved in ethyl acetate-dichloromethane and applied to the column. The column is then eluted with ethyl acetate to give 0.25 g of product as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[N:24]1C=CC=C(NN)[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:25]=[N:24][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: NNc1cccnc1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1

Procedure:
807 mg (2.90 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 464 mg (3.19 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 353 mg (38% of theory) of the title compound is obtained.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=CCC[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:2]([CH:14]1[CH2:15][CH2:10][CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[CH2:3][CH:4]=[CH2:5]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCCC(CCC=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 1 L oven-dried round-bottom flask was charged with methyltriphenylphosphonium bromide (9.30 g, 26.0 mmol) and THF (250 mL) and cooled to −70° C. A solution of BuLi (2.5 M in hexanes, 10.4 mL, 26.0 mmol) was added dropwise, and the reaction mixture was stirred for 1 h. A solution of tert-butyl 3-(3-oxopropyl)piperidine-1-carboxylate (4.19 g, 17.4 mmol) in THF (15 mL) was added, and the reaction mixture was slowly warmed to RT and stirred for 3 days. The reaction mixture was quenched with water and concentrated to remove THF. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried with anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (95 hexane/5 EtOAc) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ 5.83-5.77 (m, 1H), 5.0{tilde over (4)} 4.95 (m, 2H), 3.9{tilde over (2)} 3.88 (m, 2H), 2.77 (s, br, 1H)), 2.6{tilde over (0)} 2.35 (m, 1H), 2.1{tilde over (1)} 2.07 (m, 2H), 1.81 (m, 1H), 1.6{tilde over (4)} 1.58 (m, 1H), 1.5{tilde over (0)} 1.20 (m, 13H), 1.2{tilde over (5)} 1.00 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[N:24]#[C:25]Br.C(=O)(O)[O-].[Na+].[K+].[Br-]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([N:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:10][N:11]=[C:25]2[NH2:24])[CH:7]=1
Reactant: N#CBr
Reactant: COc1ccc(Cl)cc1NC(=NN)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cl)cc1-n1c(N)nnc1-c1ccc(C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide (1.5 g, 4.36 mmol) was dissolved in 1,4-dioxane (7 ml) and cyanogen bromide (475 mg, 4.48 mmol) was added. A solution of sodium bicarbonate (380 mg in 7 ml of water) was added dropise at room temperature and the reaction mixture was stirred for 3 h. An additional 7 ml of water was added to the heterogenous reaction mixture before filtration and rinse with water. Recrystallization from acetonitrile gave 922 mg (57.3%) mp 247-248° C.; IR(KBr, υ=cm−1) 3416, 3076, 3052, 1652, 1561, 1504, 1322, 1110; 1 H NMR (300 MHz, DMSO-d6) δ 3.60 (3H, s), 5.92 (2H, s), 7.22 (1H, d, J=9.5 Hz), 7.47 (2H, d, 8.3 Hz), 7.54-7.57 (2H, m), 7.67 (1H, d, J=8.4 Hz).; MS(DCl)m/z: 369(MH+). Anal. calcd. for C16H12ClF3N4O: C, 52.12; H, 3.28; N, 15.19. Found: C, 52.19; H, 3.20; N, 15.29.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([NH:14][C:15]2[CH:46]=[CH:45][C:18]3[CH:19]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:20][CH2:21][N:22]([C:24](=[O:39])[NH:25][CH2:26][CH2:27][CH2:28][C:29]4[N:34]=[C:33]5[NH:35][CH2:36][CH2:37][CH2:38][C:32]5=[CH:31][CH:30]=4)[CH2:23][C:17]=3[CH:16]=2)=O)=CC=1)([O-])=O>C(O)C.[Pd]>[C:12](=[N:14][C:15]1[CH:46]=[CH:45][C:18]2[CH:19]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:20][CH2:21][N:22]([C:24](=[O:39])[NH:25][CH2:26][CH2:27][CH2:28][C:29]3[N:34]=[C:33]4[NH:35][CH2:36][CH2:37][CH2:38][C:32]4=[CH:31][CH:30]=3)[CH2:23][C:17]=2[CH:16]=1)=[O:11]
Reactant: COC(=O)CC1CCN(C(=O)NCCCc2ccc3c(n2)NCCC3)Cc2cc(NC(=O)OCc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCN(C(=O)NCCCc2ccc3c(n2)NCCC3)Cc2cc(N=C=O)ccc21
Reaction time: 4 h

Procedure:
To a stirring solution of methyl 2-(8-{[(4-nitro phenyl)methoxy]carbonylamino}-2-[N-(3-(1,2,3,4-tetrahydropyridino[2,3-b]pyridin-7-yl)propyl) carbamoyl]-1H,3H,4H,5H-benzo[e]azepin-5-yl)acetate in ethanol (0.05 M) at room temperature was added 10% Pd/C (0.10M). After stirring 4 hr, under hydrogen, at balloon pressure, the reaction mixture was filtered through celite. The reaction solvent was removed by rotary evaporation. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 480 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:23])([CH3:22])[C:7](=[O:21])[N:8]2[C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:36]([O:35][C:33](=[O:34])[CH2:32][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][NH:13][C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([CH3:23])([CH3:22])[C:7]2=[O:21])=[O:12])[CH2:16][CH2:17]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1(C)C(=O)N(C(=O)NCC2CCNCC2)c2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCC(CNC(=O)N2C(=O)C(C)(C)c3ccc(F)cc32)CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A solution of 6-fluoro-3,3-dimethyl-2-oxo-N-(piperidin-4-ylmethyl)indoline-1-carboxamide (200 mg, 0.63 mmol, step 2 in Example 17) and triethylamine (114 μL, 0.82 mmol) in tetrahydrofuran (3 mL) was stirred at 0° C., it was slowly added tert-butyl bromoacetate (111 μL, 0.75 mmol). The reaction mixture was stirred at room temperature for 5 h and at 35° C. for 4 h. It was further added triethylamine (17 μL, 0.12 mmol) and tert-butyl bromoacetate (18 μL, 0.12 mmol). The solution was stirred at room temperature overnight. The resulting solution was added sat. sodium bicarbonate. It was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with ethyl acetate/hexane (1:10 to 1:6) to give 203 mg (74%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([O:35]C)=[O:34])[C:23]4=[O:37])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:37])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)NC(=O)C(NC(=O)OC(C)(C)C)C4)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(NC(=O)OC(C)(C)C)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Methyl 8-(3-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (43 mg, 0.083 mmol) was dissolved in methanol (2 mL) and sodium hydroxide 1M solution in water (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 50° C. for 2 h. After cooling, the methanol was removed in vacuo. The residue was dissolved in water (5 mL) and then neutralized with 1M HCl (˜0.5 mL). The precipitate formed was stirred at room temperature overnight. The mixture was extracted with CH2Cl2 (3×4 mL). The organic layers were concentrated to afford the title compound as a yellow solid (29 mg, 69%). ESI-MS m/z: 504 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[C@@H:3]([O:5]C1CCCCO1)[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:5][C@@H:3]([CH3:4])[C:2]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH3:1]
Reactant: C[C@H](OC1CCCCO1)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Yield: 76.4 %

Procedure:
A solution of N-{3-[(S)-1,1-Dimethyl-2-(tetrahydro-pyran-2-yloxy)-propyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (1.14 g, 2.41 mmol) and pyridinium p-toluenesulfonate (120.63 mg, 0.48 mmol) in ethanol (11 mL) is stirred at 65° C. for 3 h. After this time, the reaction mixture is concentrated under reduced pressure and partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate once. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated. The resulting solid is trituated in ethanol and filtered to yield the title compound. Yield 76.4%; (400 MHz, CHLOROFORM-d) δ ppm 1.15 (3H, d), 1.28 (6H, s), 1.72 (6H, s), 1.80-1.90 (2H, m), 1.90-2.02 (2H, m), 2.26 (1H, d), 3.32-3.43 (2H, m), 3.40-3.50 (1H, m), 3.85-3.93 (1H, m), 4.00-4.10 (2H, m), 6.29 (1H, s), 9.62 (1H, s). ES-MS: m/z 389 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([F:20])([F:19])[F:18])[C:9]1=[O:21])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:29][C:30]1([CH3:42])[O:34][C@@H:33]([C:35]2[N:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:32][O:31]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.CO>[CH3:29][C:30]1([CH3:42])[O:34][C@@H:33]([C:35]2[N:36]=[CH:37][C:38]([NH:41][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]=4[C:17]([F:20])([F:19])[F:18])[C:9]3=[O:21])[CH2:3][CH:2]([CH3:22])[CH3:1])=[N:39][CH:40]=2)[CH2:32][O:31]1
Reactant: CC(C)C[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)C[C@@H](C(=O)Nc1cnc([C@H]2COC(C)(C)O2)cn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid (prepared as in Example 23, 79 mg, 0.25 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) at room temperature was treated with a solution of oxalyl chloride (2.0M in methylene chloride, 150 μL, 0.30 mmol) and stirred for 15 min. After this time, the reaction mixture was concentrated in vacuo and then diluted with methylene chloride (5 mL) and added to a flask containing a solution of 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared as in WO2004052869, Example 54, 98 mg, 0.50 mmol), 2,6-lutidine (100 μL, 0.50 mmol) in methylene chloride (2.5 mL) at room temperature. The reaction mixture was then stirred at room temperature for a period of 2 h. After this time, the reaction mixture was treated with methanol and then diluted with methylene chloride. The reaction mixture was then transferred to a separatory funnel and washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated with silica gel (2 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 40% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (54 mg, 44%) as a colorless sticky solid: HR-ES(+) m/e calcd for C24H27N4O4F3 [M+H]+ 493.2057, observed 493.2059; 1H NMR (400 MHz, CHLOROFORM-d) δ 9.37 (d, J=1.28 Hz, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=7.46 Hz, 1H), 7.82 (d, J=7.67 Hz, 1H), 7.64 (t, J=7.78 Hz, 1H), 5.20 (t, J=6.50 Hz, 1H), 5.13 (dd, J=6.93, 8.84 Hz, 1H), 4.68-4.78 (m, 1H), 4.55-4.65 (m, 1H), 4.42 (dd, J=6.82, 8.52 Hz, 1H), 3.95 (dd, J=6.29, 8.42 Hz, 1H), 2.00-2.13 (m, 1H), 1.88-2.00 (m, 1H), 1.53-1.69 (m, 1H), 1.44-1.52 (m, 6H), 0.97-1.07 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][CH:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]([NH2:16])=[O:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: NC(=O)C(N)CC(F)(F)F
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ncc(NC(CC(F)(F)F)C(N)=O)nc1Cl
Yield: 88.1 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (50 mg, 0.287 mmol), 2-amino-4,4,4-trifluorobutanamide hydrochloride (50 mg, 0.259 mmol) and DIEA (0.150 mL, 0.862 mmol) in NMP (1 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give 2-(6-chloro-5-cyanopyrazin-2-ylamino)-4,4,4-trifluorobutanamide (67 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-c2ccnn2C)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-5-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])#[N:2].N1C=CC=CC=1.[CH3:16][CH2:17][O:18]CC>C(OC(=O)C)(=O)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:17](=[O:18])[CH3:16])#[N:2]
Reactant: CCOCC
Reactant: N#CCCCCCCO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6-Cyano-1-hexanol (7.1 g, 55.8 mmol) was dissolved in 30 mL of acetic anhydride under argon atmosphere. To this material was added 5.3 mL (65.4 mmol) of pyridine dropwise and the mixture was left to stir for 2 hours. The contents of the flask were then poured into a beaker containing 50 mL of ice water and the material was stirred for 15 minutes. The mixture was transferred to a 250 mL separatory funnel and ether (100 mL) was added. After shaking the ether phase was isolated and the aqueous phase washed twice more with ether (2 ×100 mL). The combined ether phase was washed with brine, dried (MgSO4) and filtered. Evaporation (rotary evaporator and vacuum pump) provided 6-cyano-1-acetoxyhexane (the compound of formula (C)) which was used immediately in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](Br)[C:9]#[CH:10]>C(O)C>[CH2:10]([NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]#[CH:8]
Reactant: C#CCBr
Reactant: Nc1ncccn1
Solvent: CCO
Product: C#CCNc1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-aminopyrimidine (2 g, 20.67 mmol) and propargyl bromide (23 mL, 20.67 mmol) in ethanol (30 mL) was heated to reflux for about 23 hours. The formed precipitate was collected by filtration, washed with ethanol and was recrystallized from ethanol. To the vacuum dried crystals was added water (10 mL) and 10% aqueous sodium hydroxide (5 mL) and the mixture was stirred at room temperature for about 30 min. The solid was collected by filtration, washed with water and was re-crystalized from water to provide Example 642. MS (ESI): m/z 134 (M+H)+.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:8]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:10])=[CH:3][CH:2]=1
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(-c2ccccc2)cc1
Product: CC(C)CNC(=O)C(NC(=O)OC(C)(C)C)c1ccc(-c2ccccc2)cc1
Yield: 55 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)acetic acid and isobutyl amine. Yield: 55%. 1H NMR (400 MHz, dMSO): δ 0.76-0.78 (d, 6H), 1.38 (s, 9H), 1.63-1.66 (m, 1H), 2.84-2.92 (m, 2H), 5.30-5.22 (d, 1H), 7.25-7.27 (d, 1H), 7.35-7.37 (m, 1H), 7.43-7.51 (m, 4H), 7.61-7.66 (m, 4H), 8.14-8.17 (t, 1H); MS+H (383).