Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[N:19]1([C:18]2[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1cnc(N2CCNCC2)c(N2CCCC2)c1
Reaction time: 0.33 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-(1-pyrrolidinyl)-2-pyridinyl]piperazine (PREPARATION 47, 0.26 g) is dissolved in 1.3 ml of THF and cooled to 0°. Trifluoroacetic acid (1.3 ml) is added and the reaction is stirred at 0° for 20 min, and then warmed to 20°-25° for 20 min. Then the reaction is poured into 1N aqueous sodium hydroxide and extracted with methanol/chloroform (10/90, 2×50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.64, 6.81, 6.61, 3.05-2.94, 2.86-2.79 and 1.78-1.65 δ.
Reaction SMILES: [C:1]12C(=CC=CC=1)NC(=O)OC2=O.[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](=C)=[N-]>CCOCC>[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH3:1])=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21

Procedure:
Following the procedure set forth in Preparation A, steps (2-3), isatoic anhydride was converted to 1-heptyl-4-hydroxy-3-ethoxycarbonyl-2(1H)-quinolinone, which upon reaction with excess diazomethane in ether gave the title compound. That the expected product was obtained was confirmed by the spectral data: MS: m/e 345 (M.+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH:28]([S+:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])([CH3:30])[CH3:29].C([O-])(C)(C)C.[K+].O>C(Cl)Cl>[NH2:6][C:5]1[C:12]([Cl:14])=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([N:32]=[S:31]([CH:33]([CH3:35])[CH3:34])[CH:28]([CH3:30])[CH3:29])=[O:10]
Reactant: CC(C)[S+](N)C(C)C
Reactant: O=c1[nH]c2c(Cl)cc(Cl)cc2c(=O)o1
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 276.5 %

Procedure:
To a suspension of 6,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione (45.0 g, 70.7 mmol) in methylene chloride (500 mL) was added S,S-Diisopropyl-S-aminosulfonium 2,4,6-trimethyl-phenylsulfonate (77.6 g, 234 mmol). The reaction mixture was cooled to 0° C. and potassium tert-butanolate (8.73 g, 77.8 mmol) was added after which the reaction was allowed to come to room temperature and stirred for 16 h. Water (200 mL) and methylene chloride (50 mL) were then added, the organic phase was separated and the aqueous phase further extracted with methylene chloride (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound (62.8 g, quant.).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@H:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C:9]=1[C:25]([O:27]CC1C=CC([N+]([O-])=O)=CC=1)=[O:26])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+:42]>O1CCOCC1.O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@H:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C:9]=1[C:25]([O-:27])=[O:26])(=[O:3])[CH3:2].[Na+:42]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@@H](C)Sc3ccccc3)[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCSC1=C(C(=O)[O-])N2C(=O)[C@@H]([C@@H](C)Sc3ccccc3)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(R)-1-phenylthioethyl]-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (e 103) (10 mg) in a mixture of dioxan and water (7:3, 5 ml) was added to 5% palladium on carbon catalyst which had been prehydrogenated for 30 min. in a mixture of dioxan and water (7:3, 5 ml). The mixture was hydrogenated at slightly super-atmospheric pressure for 4 hr., when sodium hydrogen carbonate (1.9 mg) was added to the mixture. The catalyst was filtered off and washed with water (5 ml). The filtrate was evaporated in vacuo to remove most of the dioxan and the resultant mixture was diluted with water to 25 ml and extracted with ethyl acetate. The aqueous extract was washed with ethyl acetate. The u.v. spectrum of the aqueous layer showed a maximum of about 300 nm, indicating the presence of the sodium salt. The volume of the aqueous solution was reduced to about 1 ml, loaded onto a Biogel P-2 column and eluted with water to give sodium (5R,6S)-3-(2-acetamidoethylthio)-6-[(R)-1-phenylthioethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e 104).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][CH:33]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:36]([C:35]5[CH:40]=[CH:41][C:32]([O:31][CH3:30])=[CH:33][CH:34]=5)=[N:38][N:39]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Yield: 36.3 %

Procedure:
The procedure described in example 123 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (400 mg, 1.25 mmol), triethylamine (0.5 mL, 3.7 mmol) and 4-methoxy benzhydrazide (415 mg, 2.5 mmol) was used to prepare the title compound (175 mg, 37% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.71 (s, 1H), 8.16 (d, 1H), 8.0-8.1 (m, 4H), 7.75 (d, 1H), 7.45 (t, 2H), 7.1 (d, 2H), 3.88 (s, 3H), ES-MS (m/z) 386 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].IC.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:6]=[C:7]([S:21][CH3:32])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC1=NC(c2ccc(C#N)cc2)C(C(C)=O)=C(C)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile example 1; 100 mg, 0.24 mmol), 1-iodomethane (38.0 mg, 0.27 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 min acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Under a nitrogen atmosphere, 4-chloroanisole (0.30 g, 2.1 mmol), phenylboronic acid (0.37 g, 3.0 mmol), potassium phosphate n-hydrate (0.85 g), (π-allyl)palladium chloride (3.7 mg, 0.01 mmol), 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.1 mg, 0.04 mmol) obtained in Example 4 and toluene (4 ml) were placed in a reaction flask and stirred for 3 hours at 80° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give the title compound (0.35 g, 90%) as white crystal.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH2:31])[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH:31][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ncccc12

Procedure:
A mixture of 6-bromo-9H-purine (0.0712 g, 0.358 mmol), 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanamine (0.050 g, 0.18 mmol), and N,N-diisopropylethylamine (0.0623 mL, 0.358 mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product. LCMS calculated for C23H20FN6 (M+H)+: m/z=399.2; Found: 399.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][CH:37]=1)CCC>>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccco4)n3)cnc2n1
Yield: 59 %

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (from Example 34) (58 mg, 0.14 mmol) and 2-tributylstannylfuran (102 mg, 0.29 mmol) were heated at reflux overnight as described in Example 40. Purification by column chromatography on silica using 70% EtOAc/isohexanes as the eluent gave 3-[2-(furan-2-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (36 mg, 57%): m/z (ES+) 435 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:12][N:8]1[CH2:7][CH2:6][C:5]2[N:4]=[CH:3][C:2]([NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]=2[CH2:9]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCc2ncc(N)cc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCc2ncc(NC(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 53 %

Procedure:
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine (314 mg, 1.9 mmol) was dissolved in dichloromethane (10 ml) and treated sequentially with triethylamine (214 mg; 2.1 mmol) and benzoyl chloride (297 mg; 2.1 mmol). The mixture was stirred at ambient temperature until tlc showed no starting material remaining. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate, water, saturated brine, dried (anhydrous magnesium sulphate) and evaporated to dryness under reduced pressure. Chromatography through silica gel, eluting with methanol in dichloromethane (0 to 50% methanol gradient), gave the title compound as an off-white foam (269 mg; 52%)
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:29].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][K:29])=[O:25])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [K+]
Reactant: CCCN(CCCC(=O)OC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN(CCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 163.2 %

Procedure:
A round bottom flask fitted with a heating mantle and an overhead stirrer was charged with C4F9SO2N(C3H7)CH2CH2CH2COOCH3 (63.0 g; 0.143 mole), KOH (11.0 g; 0.196 mole; pellets) isopropanol (22 ml.) and deionized water (18 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)CH2CH2CH2COOK (108.6 g; 53.4% solids).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([Cl:14])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CC2C=CC1C2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-norbornene-2-carboxylic acid (Aldrich, mixture of endo and exo, 1.25 g, 9.05 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (0.99 mL, 11.31 mmol) and a catalytic amount of N,N-dimethylformamide (100 μL). The reaction mixture was stirred at ambient temperature for 2 hours and then solvent and excess oxalyl chloride were removed under reduced pressure to yield the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]=[C:14]=[O:15])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(N=C=O)c(F)cc1Cl

Procedure:
A solution of 4-chloro-2-fluoro-5-isopropoxyaniline (30 g) in toluene (100 ml) was added to a 1 mol/l phosgene/toluene solution (500 ml) at room temperature (ca. 20° C.), followed by heating under reflux for 2 hours. The mixture was concentrated under reduced pressure and the residue was distilled to give 26 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate as pale yellow crystals. M.P., 36°-37° C. B.P., 90°-91° C./3 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)CCl.[NH2:28][CH2:29][C:30]#[N:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:29]([CH2:30][NH:31][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:5]=2)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[CH:11]=1)=[O:15])#[N:28]
Reactant: N#CCN
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NCC#N)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a solution of 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.59 mmol) in CH2Cl2 (5 mL) was added EDC (0.14 g, 0.72 mmol), 4-(dimethylamino)pyridine (0.088 g, 0.72 mmol), and aminoacetonitrile (0.041 g, 0.72 mmol). The reaction mixture was stirred at room temperature for 5 h then diluted with CH2Cl2 and washed with H2O and brine. The organics were dried over Na2SO4 and concentrated. The residue was purified by SiO2 chromatography (25% EtOAc/hexanes) to obtain 0.194 g (88%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyanomethyl-amide a white solid.
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]1([CH2:12][O:13][C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:28](Br)[C:29]#[CH:30]>C(O)C.C1(C)C=CC=CC=1>[C:6]1([CH2:12][O:13][C:14]([NH:16][C:17]([C:28]#[C:29][CH3:30])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: C#CCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC#CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Yield: 41.9 %

Procedure:
A solution of sodium ethylate previously prepared from 500 mg of sodium in 20 ml of ethanol is added to 6 g of diethyl 2-[[(phenylmethoxy)carbonyl]amino]-propanedioate (prepared according to Bladon. C. M. J.Chem. Soc. Perkin. Trans I 9, 1151-1158 (1990) in 30 ml of ethanol then, after 30 minutes, 3 g of propargyl bromide at 80% in toluene is added and the reaction mixture is heated under reflux for 1 hour. The reaction mixture is then brought back to ambient temperature followed by evaporation under reduced pressure, taking up in dichloromethane, washing and drying. After evaporation under reduced pressure 6 g of the expected product is obtained which is purified by chromatography, eluting with a Cyclohexane/Ethyl acetate mixture 85/15. 2.82 g of purified product is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:38][C:34]1[CH:33]=[C:32]([C:22]2([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
N,N'-Carbonyldiimidazole (0.59 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.65 g) in dry dichloromethane (20 cc). The mixture is stirred for 90 minutes at 25° C. and a solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1.3 g) and triethylamine (1.02 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 16 hours at 25° C. and washed with water (2×250 cc) and with saturated sodium chloride solution (250 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.3 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55:45) and collecting 15-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified with isopropyl ether to give (3aRS,7aRS)-7,7-bis(3-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (0.6 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (1 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.48 g) is obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][O-:36].[Na+]>CO>[CH3:35][O:36][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1
Yield: 27.5 %

Procedure:
A cloudy solution of 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 22 mg, 0.046 mmol) and NaOMe (25% Wt, 0.75 mL, 3.3 mmol) in MeOH (0.75 mL) was heated at 100° C. for 30 mins using microwave irradiation. The cooled reaction mixture was evaporated in vacuo preparative TLC (20×20 cm×1 mm) eluting with 50% EtOAc in cyclohexane to give the title compound as a white solid (6 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([N:16]2[CH:17]=[C:13]([C:12]3[N:11]([CH3:18])[N:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:14]=[CH:15]2)=[N:21][CH:22]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 54.4 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (82 mg, 0.34 mmol), methyl 6-chloronicotinate (58 mg, 0.34 mmol) and potassium carbonate (93 mg, 0.67 mmol) in DMF (1.7 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into HCl (1 N) and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (70 mg, 55%) as an off white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-:16].[NH3+:17][CH2:18][CH2:19][CH2:20][N+:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH3:31])=[CH:23][CH:22]=1.[Br-].C(N(CC)CC)C>O>[Br-:16].[OH:14][CH:13]([CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:15][NH:17][CH2:18][CH2:19][CH2:20][N+:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH3:31])=[CH:23][CH:22]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: Cc1cc[n+](CCC[NH3+])c2ccccc12
Agent: [Br-]
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc[n+](CCCNCC(O)COc2cccc3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Compound 1 (0.17 g, 0.83 mmol) and Compound 2 (0.30 g, 0.83 mmol) in water (1 mL), triethylamine (0.10 g, 0.99 mmol) was added. The combined mixture was stirred at room temperature for 24 hours and then evaporated in the rotary evaporator to provide Compound 3 as a solid. This product was used without any workup and further purification. The structure of Compound 3 is given below: