Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[O:10][CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[C:14]#[N:15]>CN(C)C=O>[CH2:1]([O:3][CH2:4][C:5]([NH:8][C:9]1[O:10][CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[C:14]#[N:15])=[O:6])[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)c1coc(N)c1C#N
Solvent: CN(C)C=O
Product: CCOCC(=O)Nc1occ(C(C)(C)C)c1C#N
Temperature: 0 °C
Yield: 78.5 %

Procedure:
26.2 g (0.2 mole) of ethoxyacetyl chloride were added dropwise to a solution of 32.8 g (0.2 mole) of 2-amino-3-cyano-4-tert.-butyl-furan in 200 ml of dimethylformamide at room temperature. After the moderately exothermic reaction had subsided (rise in temperature from 23° C. to 38°), the reaction mixture was poured into ice-water. The solid product thereby obtained was filtered off and recrystallized, in the moist state, from a little methanol. 39.3 g of 2-ethoxyacetylamino-3-cyano-4-tert.-butyl-furan of melting point 98° C. were obtained in this manner.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19](=[S:22])([O-:21])[CH3:20].[K+].O>CC(C)=O.[I-].[K+]>[C:19]([S:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Yield: 104.9 %

Procedure:
A solution of methyl 4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (5 g, 18.82 mmol, 1.00 equiv), potassium ethanethioate (2.68 g, 23.47 mmol, 1.25 equiv) and potassium iodide (120 mg, 0.72 mmol, 0.04 equiv) in acetone (40 mL) was stirred at 35° C. for 30 min. Water (50 mL) was added to quench the reaction. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 6.03 g of crude methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>>[CH:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:6]=3[N:7]=2)[CH2:32][CH2:31]1)=[O:29]
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCCc4ccccc4)ncnc23)CC1
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(NCCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 181 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenethylamino-pyrimido-[5,4-d]-pyrimidine (m.p.: 198°-200° C.) and N-formyl-piperazine.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C(COC)OC>[CH3:1][CH:2]1[C:7](=[S:28])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1Oc2ccc(Cn3ccnc3)cc2NC1=O
Solvent: COCCOC
Product: CC1Oc2ccc(Cn3ccnc3)cc2NC1=S
Temperature: 25 °C
Reaction time: 46 h
Yield: 57.4 %

Procedure:
390 mg (1.603 mmol) of (±)-2-methyl-3-oxo-6-[(1-imidazolyl)-methyl]-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 42 ml of dimethoxyethane, mixed with 1.297 g (3.206 mmol) of Lawesson's reagent and stirred for 46 hours at room temperature. After the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). The fractions that are obtained by chromatography are removed from the polar contaminants by shaking with saturated sodium bicarbonate solution. 238.5 mg (57%) of the desired product is isolated, ting point 206-210° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:12]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][C:13]2([OH:11])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH3:10]
Reactant: C1CC2(CCO1)CO2
Reactant: Cc1cc(O)cc(C)c1Br
Product: Cc1cc(OCC2(O)CCOCC2)cc(C)c1Br

Procedure:
The title compound is prepared from 4-bromo-3,5-dimethylphenol and 1,6-dioxaspiro[2.5]octane following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 7): tR=1.04 min; Mass spectrum (ESI−): m/z=313 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccccc1CN
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CNCC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-bromo-1,1-diphenyl-2-propanone (0.5 g) in tetrahydrofuran (10 ml) was added to a mixture of (2-methoxy-benzyl)amine (1.13 ml) and N,N-diisopropylethylamine (0.602 ml) in tetrahydrofuran (12 ml) over 0.5 hour at room temperature. After being stirred at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure to half volume and the resulting mixture was poured into ice-water (10 ml) and extracted with ethyl acetate (10 ml×2). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3-[(2-methoxybenzyl)amino]-1,1-diphenylpropan-2-one (483 mg) as a colourless syrup.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[N:8]=[C:9]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[N:22]([CH2:29][CH2:30][CH3:31])[C:21]3=[O:32])=[O:17])[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.CO>N1C=CC=CC=1>[O:28]=[C:23]1[N:22]([CH2:29][CH2:30][CH3:31])[C:21](=[O:32])[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:9]3[N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]4=[C:7]([NH:6][S:1]([CH3:4])(=[O:3])=[O:2])[N:8]=3)=[O:17])[CH:19]=2)[NH:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(N)c4ccccn34)cc2c1=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(NS(C)(=O)=O)c4ccccn34)cc2c1=O
Yield: 32.3 %

Procedure:
0.1 ml (1.2 mmol) of mesyl chloride is added, at 0° C. under an inert atmosphere, to 0.25 g (0.4 mmol) of 6-[(1-aminoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dione in 5 ml of pyridine. After the addition of methanol, the reaction medium is concentrated under reduced pressure. The residue is taken up with dichloromethane. The organic phase is washed with a 1N aqueous solution of hydrochloric acid and then with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is recrystallized while hot from methanol, purified on a silica gel frit, elution being carried out with DMF. 0.057 g of an orange solid is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH3:11])(=[O:5])=[O:4].[Li]CCCC.[O:18]1[CH2:20][CH2:19]1>O1CCCC1>[OH:18][CH2:19][CH2:20][C:9]1[N:8]=[C:7]([CH3:11])[N:6]([S:3]([N:2]([CH3:12])[CH3:1])(=[O:4])=[O:5])[CH:10]=1
Reactant: Cc1nccn1S(=O)(=O)N(C)C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CCO)cn1S(=O)(=O)N(C)C
Temperature: -78 °C
Yield: 43.1 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N,N,2-trimethyl-1H-imidazole-1-sulfonamide (compound 282.1, 6.4 g, 33.8 mmol) in tetrahydrofuran (50 mL). This was followed by the addition of n-BuLi (2.5M in hexane) (16.3 mL, 40.6 mmol) dropwise with stirring at −78° C. The reaction mixture was stirred for 1 h at −78° C. Oxirane (12.1 mL, 242.89 mmol) was added dropwise at −30° C. The reaction mixture was stirred for 2 h at room temperature, then quenched with 10 mL of water. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc:MeOH (40:1) as the eluent to yield 3.4 g (43%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH:6]=[N:7]2.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH:6]=[N:7]2
Reactant: Cc1ccc(C)c2c1N=CCC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a flask is placed 5,8-dimethyl-4-quinolone (5.18 g, 29.9 mmol) (prepared according to Burckhalter, et al., J. Am. Chem. Soc., Vol. 70 (1948), p. 1363) with sulfuric acid (30 mL). After stirring for 10 minutes, the flask is cooled in ice and concentrated nitric acid (1.90 mL, 30.2 mmol) is added dropwise. After the addition is completed, the mixture is stirred for 15 minutes in ice. The mixture is then poured onto crushed ice and allowed to warm to room temperature. The gray solid is filtered and washed with water. The solid is recrystallized from hot methanol to give 5,8-dimethyl-6-nitro-4-quinolone.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[O:4][C:5]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)([CH3:9])[CH2:6][C:7]=1[OH:8].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]2[N:24]=[C:25]([SH:27])[N:26]=[C:19]2[N:18]=1>>[CH:10]1([C:5]2([CH3:9])[O:4][C:3](=[O:15])[C:2]([S:27][C:25]3[N:26]=[C:19]4[N:18]=[C:17]([CH3:16])[CH:22]=[C:21]([CH3:23])[N:20]4[N:24]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC1(C2CCCC2)CC(O)=C(Cl)C(=O)O1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: Cc1cc(C)n2nc(SC3=C(O)CC(C)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared from 3-Chloro-6-cyclopentyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (described in Step 2 below) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the coupling method described in Example C(4). 1H NMR (CDCl3): δ 1.54 (s, 3H), 1.55-2.32 (br m, 9H), 2.59 (m 1H), 2.64 (s, 3H), 2.71 (s, 3H), 2.96 (m, 1H), 6.77 (s, 1H). ESIMS: MH+ 375.10, MH− 373.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:17]3[C:12]([CH3:23])([C:13]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=4[CH2:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:24])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C@@H:17]3[C@:12]([CH3:23])([C:13]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10][C:9]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN2C(=O)CCC3(C)C2=CCc2cc(Cl)ccc23)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CC[C@@]3(C)c4ccc(Cl)cc4CC[C@H]23)cc1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a stirred solution of subtitle compound from Step B (693 mg) in CH2Cl2 (2.5mL) under a nitrogen atmosphere was added triethylsilane (1.4 ml) The reaction mixture was stirred for 15 minutes. To the solution was added 1.5 mL of trifluoroacetic acid and the reaction mixture stirred at room temperature overnight. The reaction mixture was partitioned between CHCl3 and saturated NaHCO3. The organic phase was dried over Na2SO4 and the solvent removed under vacuum. The residue was purified by chromatography on SiO2 (25% ethyl acetate in hexanes as eluent). The product containing fractions were evaporated under vacuum to afford 459 mg of the subtitle compound as a foam. Melting point 55°-60° C.
Reaction SMILES: C(=O)([O-])OCC[CH2:5]/[C:6](/[CH3:16])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH2:5]/[C:6](/[CH3:16])=[CH:7]/[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)[S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])=[CH:37][CH:38]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCS(=O)(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: C/C(=C\c1cccc(C#N)c1)CCCOC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C/C(C)=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a suspension of [3-(3-cyanophenyl)-2-methyl-2-(E)-propenyl]ethyl carbonate (1.10 g) and N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]ethanesulfonamide (1.15 g) in tetrahydrofuran (9 ml) were added tris(dibenzylideneacetone)palladium chloroform complex (78 mg) and triphenylphosphine (39 mg) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=12/1 as an eluant to give the desired compound (0.58 g, yield 36%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][N:28]3C(=O)C4C(=CC=CC=4)C3=O)(=[O:25])=[O:24])[CH2:19][CH:18]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1.NN>C(O)C.CS(C)=O>[NH2:28][CH2:27][CH2:26][S:23]([N:20]1[CH2:19][CH:18]=[C:17]([C:5]2[N:6]=[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=3)[C:2]([NH2:1])=[N:3][CH:4]=2)[CH2:22][CH2:21]1)(=[O:25])=[O:24]
Reactant: Nc1ncc(C2=CCN(S(=O)(=O)CCN3C(=O)c4ccccc4C3=O)CC2)nc1-c1nc2ccccc2[nH]1
Agent: NN
Solvent: CCO
Solvent: CS(C)=O
Product: NCCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 80 °C
Yield: 22.3 %

Procedure:
To a suspension of 2-(2-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)ethyl)isoindoline-1,3-dione (24 mg, 0.045 mmol) in ethanol (240 μL) was added hydrazine (1.5 mg, 1.4 μL, 0.045 mmol), and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and was dissolved in 0.5 ml of DMSO and purified via reverse phase HPLC using 1 to 99% MeOH in H2O 2O (0.05% HCl as modifier) to obtain 5-(1-(2-aminoethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(1H-benzo[d]imidazol-2-yl)pyrazin-2-amine (4 mg, 18%). 1HNMR (400 MHz, MeOD) δ 8.59 (s, 1H), 8.12-8.03 (m, 2H), 7.78 (dd, J=6.1, 3.2 Hz, 2H), 7.16 (s, 1H), 4.43 (d, J=2.1 Hz, 2H), 3.95 (t, J=5.6 Hz, 2H), 3.81-3.67 (m, 4H), 3.12 (s, 2H). LC/MS m/z 400.0 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:20]([O:24][C:25]([N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:32][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1=Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of indene (5.1 ml, 0.04 mol) in dry tetrahydrofuran (15 ml), cooled in an ice bath and maintained under an atmosphere of nitrogen, was added lithium bis (trimethylsilyl) amide (82 ml of a 1.0M solution in tetrahydrofuran, 0.08 mol), over 15 minutes. The mixture was stirred in the cold for 30 minutes, then added dropwise to a solution of N-tert-butyloxycarbonylbis (2-chloroethyl)amine (9.9 g, 0.04 mol) in tetrahydrofuran (200 ml), at 0° C. The mixture was stirred for 2 hours at this temperature, then allowed to warm to ambient temperature and stirred for a further 30 minutes. The solvent was removed in vacuo to leave a dark oil, which was chromatographed using 5:1 petrol:ether as the eluant, to give 1'-(tert-butyloxycarbonyl)spiro[indene-1,4'-piperidine] (7.1 g, 58%) as a pale yellow solid. N.M.R. (CDCl3)δ 1.28 (2H, d, J=12 Hz), 1.50 (9H, s), 2.00 (2H, t of d, J=12 and 4 Hz), 3.13 (2H, t of d, J=12 and 2 Hz), 4.20 (2H, m), 6.79 (1H, d, J=6 Hz), 6.84 (1H, d, J=6 Hz), 7.30 (4H, m).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:25]1[CH:26]=[C:19]([F:18])[C:20]([C:21]#[N:22])=[CH:23][C:24]=1[F:28])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c(C#N)cc1F
Reaction time: 0.25 h
Yield: 188.7 %

Procedure:
To a suspension of NaH (2.6 g, 64 mmol, and 60.0% dispersion in oil) in DMF (80 mL) was added a solution of di-tert-butyl malonate (3.57 g, 16.50 mmol) in DMF (20 mL) at 0° C. and this was stirred for 15 min. Subsequently, 2,4,5-trifluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 h at 80° C. and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give 10.0 g of di-tert-butyl(4-cyano-2,5-difluorophenyl)propanedioate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J=5.5, J=5.4 Hz, 1H), 7.37 (dd, J=5, J=6 Hz, 1H), 4.84 (s, 1H), 1.50 (s, 18H). LC-MS (IE, m/z): 298.2 [(M+1)]+-t-Bu].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]#[N:15])=[CH:5][CH:4]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[C:14]([C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=1)#[N:15]
Reactant: N#Cc1cccn1-c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1cccn1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
7.0 g (65.1 mmol) 1-(4-(bromomethyl)phenyl)-2-cyanopyrrole (prepared according to P. R. Bovy et al., J. Med Chem. 1993, 36, 101) and 22.0 g (119 mmol) potassium phthalimide were dissolved in 260 ml dry DMF and stirred at 70° C. for 10 h. It was cooled to room temperature, and 600 ml ice-cold water were added. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate, and evaporated in vacuo. The remaining oil solidified upon standing, and it was stirred with t-butylmethylether to give pale yellow crystals of the title compound, which were filtered with suction and dried in vacuo,
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]=[CH:12][N:11](C(OC(C)(C)C)=O)[N:10]=2)=[N:6][C:7]=1[CH3:8].[CH:21]([N:24]1[C:29]2=[N:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:33]=[C:28]2[NH:27][CH2:26][C:25]1=[O:43])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]([N:24]1[C:29]2=[N:30][C:31]([C:2]3[C:7]([CH3:8])=[N:6][C:5]([C:9]4[NH:13][CH:12]=[N:11][N:10]=4)=[CH:4][CH:3]=3)=[CH:32][N:33]=[C:28]2[NH:27][CH2:26][C:25]1=[O:43])([CH3:23])[CH3:22]
Reactant: CC(C)N1C(=O)CNc2ncc(B3OC(C)(C)C(C)(C)O3)nc21
Reactant: Cc1nc(-c2ncn(C(=O)OC(C)(C)C)n2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 100 °C
Yield: 41 %

Procedure:
1-Isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (alternate approach). 7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), bis(pinacolato)diboron) (1 equiv), potassium acetate (3 equiv) and bis(1,1′-bis(diphenylphosphino)ferrocene)palladium (0.01 equiv) were combined in dioxane, degassed with nitrogen and heated to 95° C. under nitrogen. Dilution with ethyl acetate, filtration through Celite, concentration, trituration with ethyl acetate and hexanes, filtration and drying gave the boronate ester in 60% yield. tert-Butyl 3-(5-bromo-6-methylpyridin-2-yl)-1H-1,2,4-triazole-1-carboxylate (1 equiv), 1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.2 equiv), tetrakis(triphenylphosphine)palladium(0) (0.05 equiv), sodium carbonate (3 equiv) were combined in (3:1) dimethyl acetamide and water. The mixture was degassed and heated to 100° C. overnight. Standard ethyl acetate/water work up and subsequent trituration in ethyl acetate gave the desired product in 41% yield.
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]3[CH:21]=[CH:22][N:23]=[C:11]23)=[C:5]([F:24])[CH:4]=1)#[N:2].[CH2:25](Br)[C:26]#[CH:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[C:8]([O:9][CH2:27][C:26]#[CH:25])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[N:12]3[CH:21]=[CH:22][N:23]=[C:11]23)=[C:5]([F:24])[CH:4]=1)#[N:2]
Reactant: C#CCBr
Reactant: N#Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n3ccnc23)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1C#N

Procedure:
A mixture of 8-(4-cyano-2-fluoro-5-hydroxyphenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.23 g), propargyl bromide (0.16 g), potassium carbonate (0.14 g) and acetonitrile (15 ml) was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure. The residue was added with water and extracted with ethyl acetate. The extract layer was washed with water and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from diisopropyl ether to give the compound of interest (0.17 g) as a milk white crystal.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:13]([CH3:17])([C:15]#[CH:16])C.[F-].Cl.[CH2:21](N(CC)C1C=CC=CC=1)C>>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]2[C:5]=1[O:12][C:13]([CH:15]([CH3:16])[CH3:21])=[CH:17]2
Reactant: CCN(CC)c1ccccc1
Reactant: C#CC(C)(C)Oc1cc(C=O)ccc1OC(F)F
Agent: Cl
Agent: [F-]
Product: CC(C)c1cc2c(C=O)ccc(OC(F)F)c2o1

Procedure:
5.5 g of 4-difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy)benzaldehyde are refluxed with 7.2 g of cesitum fluoride for 12 h with nitrogen aeration in 30 ml of N,N-diethylaniline. After cooling, the mixture is stirred into 300 ml of 4 N hydrochloric acid, the resulting emulsion is extracted three times with 50 ml of ethyl acetate, and the organic extracts are combined, dried over calcined potassium carbonate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene. After evaporating the appropriate fractions, the title compound is obtained as an oil.