Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]1[C:19](=[O:44])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[CH:29][C:28]2=[O:42])=[CH:23][C:22]=1[F:43])=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]1[C:19](=[O:44])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:29][C:28]2=[O:42])=[CH:23][C:22]=1[F:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)OC(C)(C)C)cc2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)O)cc2=O)cc1F
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 67.8 %

Procedure:
A solution of 49 mg (0.08 mmol) of (1SR,2SR,3RS)-2-[4-(4-tert-butoxycarbonylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylic acid ethyl ester in 3 ml of 1,2-dichloromethane was treated with 28 ul of trifluoroacetic acid and stirred at 75° C. during 40 min. Evaporation of the solvents gave 31 mg (69%) (1SR,2SR,3RS) 2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylic acid ethyl ester. Off-white solid. MS: 571 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[O:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:19]1[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)c(Cl)c1

Procedure:
The title compound 3.05 g (quantitative) was obtained in a manner similar to the Manufacturing Example 25 by use of 3,4-dichloronitrobenzene and 1,4-dioxa-8-azaspiro[4.5]decane, instead of 3,4-difluoronitorobenzene and N-methylpiperazine, respectively.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=1)[OH:21])([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=1)=[O:21])([O-:13])=[O:12]
Reactant: COc1cc(C(O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
Anhydrous dimethylsulphoxide (1.2 ml) in anhydrous dichloromethane (20 ml) was added dropwise to a stirred, cooled (-75° C.) solution of oxalyl chloride (0.7 ml) in anhydrous dichloromethane (100 ml) under a nitrogen atmosphere. After 5 minutes a solution of (2-nitrophenyl)-(5-bromo-2-methoxypyridin-4-yl)methanol (2.5 g) in anhydrous dichloromethane (70 ml) was added dropwise keeping the temperature of the reaction mixture below -72° C. After a further 15 minutes triethylamine (5.3 ml) was added dropwise and the reaction mixture stirred at -75° C. for 10 minutes then the cooling bath was removed and the mixture allowed to warm to room temperature. Water (50 ml) was added, the organic layer separated, washed with water then dried (sodium sulphate) and evaporated to dryness. The product was dissolved in dichloromethane, treated with activated charcoal, filtered, evaporated to dryness, then recrystallised from dichloromethane/petroleum ether (60-80) to afford the title compound as a pale yellow solid (2.4 g). mp 128°-131° C. Rf =0.9 in 10% diethyl ether/dichloromethane on silica plates; 1 H NMR (360 MHz, CDCl3) δ 3.91 (3H, s), 6.69 (1H, s), 7.59 (1H, dd, J=1.5 and 7 Hz), 7.74 (1H, dt, J=1.5 and 7 Hz), 7.79 (1H, ddd, J=1.5 and 7 Hz), 8.13 (1H, dd, J=1.5 and 7 Hz), 8.38 (1H, s); IR (KBr) 1705 and 1695 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:17]([C:11]1[CH:12]=[CH:13][C:14]([C:7]([CH2:8][C:2]([CH3:1])([CH3:10])[CH2:3][C:4]([OH:6])=[O:5])=[O:9])=[CH:15][CH:16]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)CC(C)(C)CC(=O)O)cc1
Temperature: 25 °C

Procedure:
First, 3,3-dimethylglutaric anhydride (25 g, 0.176 moles) is heated with 1-phenylheptane (150 ml) and anhydrous aluminium chloride (51.6 g, 0.387 moles) at 90°-100° C. for 1 hour. The reaction mixture is cooled to room temperature, poured into a mixture of ice water (500 ml) and concentrated hydrochloric acid (100 ml), and extracted with ether (3×150). The combined ether extracts are dried over anhydrous magnesium sulfate and filtered. Ether is removed under reduced pressure and the resulting solution chromatographed on silica gel (hexane and then hexane:ether:acetic acid at 80:20:1) to yield 4-(4-heptylbenzoyl)-3,3-dimethyl butanoic acid (17.67 g), m.p. 41°-42° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][CH2:20][SH:21]>CC#N.O>[CH2:20]([S:21][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)[CH3:19]
Reactant: CCS
Reactant: CC(=O)Nc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCSCc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of N-(3-(bromomethyl)phenyl)acetamide (6.6 g, 29 mmol) in CH3CN (50 mL) and water (10 mL) was added K2CO3 (6 g, 43 mmol) and EtSH (1.79 g, 29 mmol). The mixture was stirred at r.t. overnight. After removal of the solvent, the residue was extracted with EtOAc, dried and concentrated to give the crude product. The crude was purified by silica gel chromatography (petroleum ether:EtOAc=1:0 to 10:1) to give N-(3-(ethylthiomethyl)phenyl)acetamide (3.4 g, 56% yield) as a light yellow solid. 1H NMR: (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.41 (s, 1H), 7.34 (d, 1H), 7.22-7.17 (m, 1H), 7.01 (d, 1H), 3.61 (s, 2H), 2.41-2.34 (m, 2H), 2.11 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[N:28]=[CH:27][N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:48])[N:10]1[CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH:50]1[NH:55][S:56]([CH3:59])(=[O:58])=[O:57].Cl.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[N:28]=[CH:27][NH:26][N:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:48])[N:10]1[CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH:50]1[NH:55][S:56]([CH3:59])(=[O:58])=[O:57]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2nc[nH]n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(1-trityl-1H-1,2,4-triazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 7.5 ml of methanol was added dropwise 0.25 ml of concentrated hydrochloric acid under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 282 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(1H-1,2,4-triazol-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([CH2:29][CH2:30][C:31](O)=[O:32])=[CH:27][O:26][N:25]=2)=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:28]2[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[N:25][O:26][CH:27]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2conc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.76 g), 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.66 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.49 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (1.14 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–90° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccc3)no2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2cc(C3CCNCC3)on2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
tert-Butyl 4-(3-phenylisoxazol-5-yl)piperidine-1-carboxylate (225 mg, 0.78 mmol) was diluted in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added to the mixture. Reaction stirred at room temperature for 1 hour. Mixture was diluted with dichloromethane and then concentrated in vacuo. Residue was treated with aqueous sodium bicarbonate. Mixture was extracted 2× ethyl acetate. Combined extracts were washed 1× water, 1× brine. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 76% yield. MS m/e (M+H)+=229.1.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1[nH]c(-c2ccccc2)cc1=O
Product: Cn1nc(-c2ccccc2)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
2-Methyl-5-phenylpyrazol-3-one (7.9 g, 0.0429 mol) is added to phosphorus oxychloride (15.3 g). The mixture is stirred at 120°C to 135°C for 8 hours, then poured into ice water, made alkaline and extracted with methylene chloride. The solution is evaporated in vacuo at 90°C to yield 8.0 g (93.8%) of an oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:32]1[CH:36]=[C:35]([CH:37]=O)[N:34]=[CH:33]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:37][C:35]4[N:34]=[CH:33][NH:32][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: O=Cc1c[nH]cn1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]cn4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 1-H-imidazole-4-carboxaldehyde (8 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[C:4]([CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([N:29]([CH2:39][CH3:40])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:26]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]2[N:24]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:21][C:3]1[C:2]([NH:1][C:23]2[N:28]=[C:27]([N:29]([CH2:39][CH3:40])[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C:26]3=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]3[N:24]=2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(C#N)cc(N)c2Cl)C1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(C3CN(C(=O)OC(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 100 °C
Yield: 67.4 %

Procedure:
A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate (Example 357D)(154 mg, 0.500 mmol), 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 10)(172 mg, 0.500 mmol), Cs2COs (326 mg, 1.00 mmol), DPPF (27.7 mg, 0.050 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (29 mg, 0.050 mmol), and Pd(OAc)2 (34 mg, 0.150 mmol) in a microwave vial was flushed with nitrogen. Dioxane (5 mL) was added and vial was sealed and heated at 100° C. for 3 hr. After cooling to room temperature, the reaction was partitioned between EtOAc and water and then filtered through celite. The solvent was removed and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded tert-butyl 3-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)-imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)azetidine-1-carboxylate (207 mg, 67% yield) as a foam. It was dissolved in DCM (0.6 mL) and anisole (30 μL, 0.272 mmol) and TFA (0.4 mL) were added. After 2 hr, the solvent was removed and the residue was applied onto an SCX cartridge using a 1:1 mixture of DCM and MeOH. This was washed with MeOH and eluted with a 1:1 mixture of 1N NH3 in MeOH and DCM to give crude 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (70 mg). A sample was purified by preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound. This was converted to the mono HCl salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]#[CH:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]([CH2:32][CH2:33][OH:34])=[N+:30]=[N-:31].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]1[N:31]=[N:30][N:29]([CH2:32][CH2:33][OH:34])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NCCO
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCO)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.9 %

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-prop-2-yn-1-yl-L-glutamate (150 mg, 377 μmol) and 2-azidoethanol (49 mg, 566 μmol) were dissolved in tetrahydrofuran (3.75 ml). To the solution, copper(I) iodide (7.2 mg, 38 μmol) and N,N-diisopropylethylamine (79 μl, 453 μmol) were added and the mixture was stirred for 12 h at room temperature. The mixture was then concentrated in vacuo and the residue was purified by preparative reversed phase HPLC to yield 62 mg (34%) of the product.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1Br>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:29]2[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=2[Cl:31])[C:7]1=[O:8])[CH3:23]
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2cc(Cl)ccc2Cl)c2c1cc(I)cc2C(F)(F)F
Yield: 51 %

Procedure:
The title compound (137 mg, 51%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (200 mg, 0.454 mmol) and 2,5-dichlorobromobenzene by the procedure similar to that described Example 92(1).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1C=NO.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:15]#[N:17])=[CH:8][CH:9]=1)([OH:2])=[O:14]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(N)cc1C=NO
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: N#CNc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In 180 ml of tetrahydrofuran was dissolved 17.12 g of 4-amino(N-hydroxyimino)methylbenzoic acid methyl ester. To the solution was added 12.12 g of triethylamine. To the mixture was added dropwise, at 0° C. (ice bath), 12.65 g of methanesulfonyl chloride. The mixture was stirred for one hour at 0° C. then concentrated under reduced pressure. To the concentrate was added methanol. The resulting crystalline precipitate was collected by filtration and dissolved in 100 ml of methanol. To the solution was added, while stirring at room temperature, a solution of 12 g of sodium hydroxide in 100 g of water. The methanol was distilled off under reduced pressure. To the residue was added 700 ml of water. To this mixture was added, while stirring at room temperature, 80 ml of 4N HCl. The resulting crystalline precipitate was collected by filtration to give 13.12 g of the title compound as a colorless crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)cc2)c2c(c1)OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (366 mg, 3.96 mmol) and 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (187a) (128 mg, 0.396 mmol) to give a white solid (121 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1 H) 7.56-7.69 (m, 2 H) 7.21-7.33 (m, 1 H) 6.97-7.09 (m, 4 H) 6.79 (d, J=2.02 Hz, 1 H) 3.75 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H20N4O3 m/z 389.20 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]=1[Cl:8].C([Mg]Cl)(C)C.C1COCC1.Cl[C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOCC>C1COCC1.CCOC(C)=O>[Br:9][C:6]1[C:7]([Cl:8])=[C:2]([C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]([CH3:11])=[N:4][C:5]=1[CH3:10]
Reactant: Cc1nc(C)c(Br)c(Cl)c1Br
Reactant: CCOC(=O)C(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred mixture of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (14.94 g, 49.9 mmol) and Cu(I)Br Me2S (0.513 g, 2.495 mmol) in THF (50 mL) was added drop wise 2M iPrMgCl/THF (26.2 ml, 52.4 mmol) at −30° C. over 5 min. Then, the resulting slurry was warmed to −10° C. over 30 min and stirred for 30 min. The homogeneous brown reaction mixture was rapidly transferred via cannula to a solution of ethyl 2-chloro-2-oxoacetate (6.14 ml, 54.9 mmol, degassed for 5 min by bubbling N2 through the solution) in THF (50 mL) maintained at −30° C. The resulting reaction mixture was stirred (1.5 h) while warming to 0° C. Then, taken up in to Et2O (200 mL), washed with 1:1 sat Na2CO3/1M NH4Cl (3×50 mL), dried (MgSO4), filtered and concentrated to give brown viscous oil. Flash chromatography using 2.5, 5 and 7.5% EtOAc/Hex afforded ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (14.37 g, 44.8 mmol, 90% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 4.42 (q, J=7.0 Hz, 2H), 2.76 (s, 3H), 2.46 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)=322.1.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[N:14]([CH3:25])[C:15]1[CH:20]=[N:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:25][N:14]([C:15]1[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1)[C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[NH2:8]
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N

Procedure:
To a solution of (1S,2S)-1-N,1-N-dibenzyl-2-N-methyl-2-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (285 mg, 0.647 mmol) in ethyl acetate (2 ml) and ethanol (1 ml) was added palladium on carbon (10% wt, 50% wet, 100 mg, 0.094 mmol). The resulting mixture was stirred under a balloon of hydrogen gas for 18 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.