Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([OH:17])[C:9]=1[OH:18])=[O:7].I[CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[CH2:25]([O:18][C:9]1[C:10]([O:17][CH2:22][CH2:4][CH2:5][CH3:6])=[C:11]([O:15][CH3:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[C:6](=[O:7])[C:5]1[C:4]([Cl:3])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCI
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c(OC)cc(C)c(C(=O)c2c(Cl)cccc2Cl)c1OCCCC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodiumhydride (0.4 g; 60 %; 10 mmol) is added with stirring to a solution of 2,6-dichloro-2',3'-dihydroxy-4'-methoxy-6'-methyl-benzophenone (1.64 g; 5 mmol) in tetrahydrofurane. The solvent is evaporated and the residue dissolved in 30 ml of dimethylformamide. 1-iodo-n-butane (4.6 g; 25 mmol) is added, the mixture is stirred at 100° C. for 8 hours and then the solvent is evaporated. The residue is shaken with toluene/2N hydrochloric acid, the organic layer separated, washed with water and the solvent evaporated. The residue is purified by chromatography (flash column filled with 35 g of silicagel; elution with 500 ml of petrolether containing 2% of ethylacetate); yellow oil (0.7 g; 32% y).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 86.9 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.6 g.), 2N aqueous solution of sodium hydroxide (100.2 ml.), methanol (100 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 22.4 g.), mp 176° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6]([C:13]([O:15]CC)=O)=[C:7]([CH:11]=O)[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].O.[NH2:29][NH2:30]>C(O)C.C(O)(=O)C>[C:1]([C:4]1[CH:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6]2[C:13](=[O:15])[NH:30][N:29]=[CH:11][C:7]=2[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(C)=O)C1c1ccc(C#N)cc1OC
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cn[nH]c(=O)c21

Procedure:
208 mg (0.565 mmol) of ethyl 5-acetyl-4-(4-cyano-2-methoxyphenyl)-2-formyl-6-methyl-1,4-dihydropyridine-3-carboxylate and 41.5 mg (0.830 mmol) of hydrazine hydrate are taken up in 6.6 ml of ethanol/acetic acid (10:1) and reacted at 100° C. for 5 h. The volatile components are removed in a rotary evaporator, and the residue is taken up in acetonitrile. The precipitated product is filtered off and dried under high vacuum. 66 mg (34.7% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:17]I.[H-].[Na+]>CN(C=O)C>[CH3:17][N:3]1[CH:4]=[N:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:7][CH:2]1[Cl:1]
Reactant: Fc1ccc(Nc2ncnc(Cl)n2)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C=NC(Nc2ccc(F)c(Cl)c2)=NC1Cl
Reaction time: 3 h

Procedure:
To 2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine (1.7 g, 6.56 mmol) and MeI (1.5 mL) in DMF (20 mL) under a nitrogen atmosphere was added NaH (60% dispersion, 0.53 mg, 13.3 mmol). The mixture was stirred for 3 h. The reaction was quenched by the addition of water and the organic extracts are taken up in EtOAc, dried over anh. MgSO4 and concentrated under reduced pressure. The crude was purified via medium pressure liquid chromatography using CH2Cl2 as the solvent system to give N-methyl-2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine.
Reaction SMILES: [C:1](Cl)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.Cl.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=[O:24])[CH2:22][NH2:23])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[C:1]([NH:23][CH2:22][C:21]([C:20]1[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:24])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: COc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCC(=O)NCC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a solution of 22.0 g (108 mM) of undecanoyl chloride in 185 ml of pyridine, 22.2 g (110 mM) of 4-methoxyphenacylamine hydrochloride was gradually added in 30 minutes under cooling and stirring below -5° C., followed by stirring for 30 minutes below -5° C. and heat-refluxing of 1 hour under stirring. After the reaction, the reaction mixture was cooled to room temperature and poured into 1 liter of cool water to precipitate a crystal. The crystal was recovered by filtration, washed with water and recrystallized from ethanol to obtain 13.9 g of decanoyl-4-methoxyphenacylamine (Yield: 38.8%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[N+:13]=[N-:14]
Reactant: Clc1nccc2ncccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nccc2ncccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 5-chloro-1,6-naphthyridine (3.3 g, 20.1 mmol) in DMF (40 mL) was added sodium azide (6.0 g, 88.5 mmol). The mixture was stirred at 80° C. for 4 h. The mixture was then poured into water (120 mL). The aqueous phase was extracted with EtOAc (150 mL×4). The combined organic layers were washed with brine (100 mL×3), dried over sodium sulfate, and concentrated under reduced pressure to give 3.4 g of the crude product as a brown solid. ESI MS: m/z 172 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CS(C)=O.CCOCC>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cc(F)cc(F)c1
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc(F)cc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 3,5-difluoro-benzonitrile (2.78 g, 20 mmol) and p-methoxybenzyl amine (5.74 ml, 44 mmol) in DMSO (20 ml) was stirred for 8 hr. in an oil bath (100-110° C.). After cooling to room temperature, the mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexane (from 1:13 to 1:10)) to afford 3.92 g (76%) of a white solid. m.p. 93-94° C.; 1H NMR (200 MHz, CDCl3) δ 3.61 (3H, s), 4.04 (2H, s); 4.16 (1H, br. s), 6.27 (1H, m), 6.42-6.47 (2H, m), 6.69 (2H, d, J=7.2 Hz), 7.06 (2H, d, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 57.5 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (60 mg) was prepared by following General Procedure F starting from 2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), 2-methoxyethylamine (21 mg), HBTU (114 mg), and DIEA (65 uL). LC/MS: m/z 418.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.48 (t, 1H), 8.05 (s, 1H), 7.95 (dd, 1H), 7.77 (d 1H), 7.58 (dd, 1H), 7.47 (d, 1H), 3.61 (bs, 3H), 3.50-3.39 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1S,2R)-2-amino-1,2-diphenylethanol (3.15 g) was dissolved in dichloromethane (45 ml) and stirred at room temperature. Ethyl bromoacetate (3.0 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (2.31 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (3.41 g, 77%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@H:36]([CH2:38][OH:39])[CH2:35][O:34]1.[CH3:41][C:42]1([CH3:49])[O:46][C@@H:45]([CH2:47]O)[CH2:44][O:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][OH:39])[CH2:35][O:34]1.[CH3:41][C:42]1([CH3:49])[O:46][C@@H:45]([CH2:47][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:44][O:43]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 4 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Reaction SMILES: C([Li])=C.[Li]C[CH2:6][CH2:7][CH3:8].C([Sn](C=C)(C=C)C=C)=C.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=C[N:20]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C>[CH:7]([C:6]1[N:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[N:22]=1)=[CH2:8]
Reactant: [Li]CCCC
Reactant: Clc1cc(Cl)ncn1
Agent: C=C[Sn](C=C)(C=C)C=C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C=C
Solvent: CCOCC
Product: C=Cc1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Vinyl lithium (10 mmol; generated from the reaction of nBuLi with tetravinyltin in diethyl ether) was added to a solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) in diethyl ether (70 mL) under an argon atmosphere at −30° C. The reaction mixture was quenched with acetic acid (600 mL) and water (200 mL) after stirring for 60 min. DDQ (2.27 g, 10 mmol) was added and the reaction mixture was warmed to 0° C. and stirred for 2 hr. The brownish slurry was then washed three times with 1M NaOH, once with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure afforded a dark brown tar from which 2-vinyl-4,6-dichloropyrimidine was isolated by flash chromatography (10% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1>O>[ClH:1].[ClH:1].[ClH:1].[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: Clc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNCc3ccc(Cl)cc3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
The operation is carried out as in Stage 3 of Example 7 starting from 242 mg of the product obtained in Stage 1 above and 680 mg of trans-1,4-diaminocyclohexane and the reaction medium is heated to approximately 140° C. for approximately 3 hours 30 minutes, then poured into H2O, followed by extracting with 3×10 ml of ethyl acetate and washing with 10 ml of saturated sodium chloride. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 85/15/1.5, salification is carried out with HCl/EtOH 1.4N, followed by filtering, washing with 5 ml EtOH then drying at ˜50° C.
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][C:8](C3N(C4C=CC(S(C)(=O)=O)=CC=4)N=CC=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)C.[H-].[Na+].I[CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:4]1.[O:33]1[CH2:34][CH2:35][CH2:30][CH2:31][CH2:32]1
Reactant: IC1CCOCC1
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1CCOCC1
Product: c1ccc2[nH]ncc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (0.18 g, 0.49 mmol) in N,N-dimethylformamide (6 mL) was added to a mixture of sodium hydride (29 mg, 60% in mineral oil, 0.74 mmol) and N,N-dimethylformamide (6 mL) under an atmosphere of argon, and the resulting mixture was stirred for 30 minutes. 4-iodotetrahydro-2H-pyran (0.16 g, 0.74 mmol) in N,N-dimethylformamide (6 mL) was then added and the reaction was heated at 60° C. for 50 hours. After cooling, the reaction mixture was concentrated and the residue diluted with water/acetonitrile (40 mL) and filtered (0.45 μm). The product was purified by preparative HPLC using a gradient of 20-80% acetonitrile:water (with 0.1% formic acid and a flow rate of 45 mL/min to afford 10 mg (4.6%) of 3-ethyl-6-{1-[4-methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1 (tetrahydro-2H-pyran)-1H-indazole as a yellow solid. LC/MS (EI) tR 4.54 (Method A), m/z 451.2 (M++1). 1H NMR (CDCl3) δ 1.4 (t, 3H); 1.9 (d, 2H); 2.4 (m, 2H); 3.0 (m, 1H); 3.1 (s, 3H); 3.6 (m, 3H); 4.1 (d, 2H); 4.5 (m, 1H); 6.6 (s, 1H); 6.9 (d, 1H); 7.2-7.3 (m, 3H); 7.5-7.7 (m, 2H); 7.8-7.9 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](Cl)[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20](N(CC)CC)[CH3:21]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:20][CH3:21])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[N:3]=1
Reactant: O=C([O-])c1cc(F)c(Cl)nc1Cl
Reactant: CCN(CC)CC
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1Cl
Yield: 92.3 %

Procedure:
Following the procedure of Example C-2, the reaction of 2,6-dichloro-5-fluoro-3-pyridinecarboxylate (2.00 g, 8.4 mmol) with 4-methylpiperazine (0.95 mL, 8.4 mmol) in acetonitrile (10 mL) in the presence of triethylamine (1.75 mL, 12.58 mmol) gave 2.34 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC([O-])(C)C.[K+].[Cl:16][C:17]1[C:18]([C:24]([NH2:26])=[O:25])=[N:19][CH:20]=[CH:21][C:22]=1Cl>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:24]([NH2:26])=[O:25])[C:17]=2[Cl:16])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1nccc(Oc2ccc(N)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 4-amino-2-fluorophenol (254 mg, 2.0 mmol) in DMF (5 mL) was added t-BuOK (359 mg, 3.2 mmol). The mixture was stirred at rt for 30 minutes. 3,4-dichloropicolinamide (420 mg, 2.2 mmol) was then added, and the mixture was microwaved at 120° C. for 2 hours. The mixture was cooled to rt, quenched with 25 mL of water. The resulted solution was extracted with EtOAc (30 mL×3) and the combined organic phases were washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a pale yellow solid (306 mg, 54.4%).
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH2:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:14][C:13]1[C:8]([CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[CH2:3][C:2]([NH2:1])=[O:39])=[N:9][C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:11][CH:12]=1
Reactant: Cc1cnc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(N3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.1 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A10) (28 mg, 0.053 mmol) in DCM (8 mL) was added TFA (2 mL) and the resulting solution was stirred at 25° C. for 24 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and 2 M NaOH (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic layers washed with brine (10 mL) and dried (MgSO4). The solvent was removed in vacuo to give a brown solid which was taken up in MeOH and purified by SCX cartridge (5 g, MeOH followed by 0.5 M NH3 in MeOH). The volatiles from the ammoniacal filtrate were removed in vacuo and the resulting solid residue suspended in cyclohexane and sonicated. The resulting suspension was filtered and the filter cake dried to give the title compound 2 as a light brown solid (8 mg, 35%); 1H NMR (400 MHz, d6-DMSO) δ 9.08 (s, 1H), 8.11 (s, 1H), 7.60 (dd, J=9.2, 2.2 Hz, 2H), 7.41 (s, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 3H), 6.92 (s, 1H), 6.85 (d, J=9.1 Hz, 2H), 4.02 (s, 1H), 3.50 (s, 2H), 3.03 (dd, J=10.1, 5.7 Hz, 2H), 2.97 (m, 2H), 2.85 (m, 4H), 2.69-2.64 (m, 2H), 2.36-2.30 (m, 2H), 2.05 (s, 3H). LCMS-A: rt 4.364 min; m/z 431.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([OH:27])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:35]Cl.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC.C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([O:27][CH3:35])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: COc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Reaction time: 0.5 h

Procedure:
A suspension of 10-(benzyloxy)-2-(4-fluorobenzyl)-4-hydroxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.50 g, 1.11 mmol) in mixture of dichloromethane (20 mL) and methanol (1 mL) at room temperature was treated with a solution of (trimethylsilyl)diazomethane in hexane. After stirring for 30 minutes, the resultant homogeneous solution was treated with a few drops of acetic acid, and the mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subject to column chromatography on silica gel eluting with 2% methanol in chloroform. Collection and concentration of the faster eluting major product provide the titled compound.
Reaction SMILES: [Na].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[C:9]([O:19]C(C)C)(=O)[CH2:10][CH2:11][C:12]([O:14]C(C)C)=O.[C:23](O)(=O)[CH3:24]>C(O)(CC)(C)C.CO.[Fe](Cl)(Cl)Cl>[O:14]=[C:12]1[C:11]2=[C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)[NH:8][C:9](=[O:19])[C:10]2=[C:7]([C:3]2[S:2][CH:6]=[CH:23][CH:24]=2)[NH:8]1
Reactant: N#Cc1cccs1
Reactant: CC(=O)O
Reactant: CC(C)OC(=O)CCC(=O)OC(C)C
Agent: Cl[Fe](Cl)Cl
Agent: [Na]
Solvent: CCC(C)(C)O
Solvent: CO
Product: O=C1NC(c2cccs2)=C2C(=O)NC(c3cccs3)=C12
Temperature: 85 °C
Reaction time: 12 h

Procedure:
Sodium metal (6.90 g, 0.30 mol) was added to 100 ml t-amyl alcohol and a small amount of iron (III) chloride (100 mg) was added. The mixture was stirred vigorously for 2 hr at 105° C. until the sodium dissolved. The solution was cooled to 85° C. and 2-thiophenecarbonitrile (22.0 g, 0.2 mol) was added. Diisopropyl succinate (16.6 g, 0.08 mol) dissolved in 10 ml of t-amyl alcohol was added dropwise to the reaction mixture over 1 hr at 85° C. The reaction mixture was stirred at this temperature for 12 hrs, then cooled to 50° C., diluted with 100 ml of methanol, and then slowly neutralized with 30 ml of glacial acetic acid and refluxed briefly, and then filtered. The residue was washed several times with hot methanol and water, and the resultant solid was dried in a vacuum oven at 50° C. A dark red color powder was obtained which was used without further purification (20 g, 83%).