Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CS(C)=O>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[NH:36][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1nc(NC2CCCC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 130 °C
Yield: 54.2 %

Procedure:
A microwave vessel was charged 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50 mg, 0.107 mmol), cyclopentanamine (456 μl, 5.35 mmol), hunig's base (93 μl, 0.535 mmol) and DMSO (1070 μl). The vial was sealed and heated to 130° C. for 2 hrs in a Biotage Initiator microwave reactor. The reaction mixture was brought to ambient temperature and then diluted with 1N HCl and Ethyl Acetate. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 10-100% EtOAc/Heptanes) to give 1-(5-chloro-6-(cyclopentylamino)-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (30 mg, 0.058 mmol, 54.3% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (br. s, 1 H) 8.72 (d, J=1.71 Hz, 1 H) 8.32-8.35 (m, 1 H) 8.18 (d, J=9.59 Hz, 1 H) 7.86 (dd, J=8.97, 2.23 Hz, 1 H) 7.66 (s, 1 H) 7.00 (d, J=9.02 Hz, 1 H) 6.77 (d, J=9.64 Hz, 1 H) 6.46 (d, J=6.79 Hz, 1 H) 5.57 (br. s., 1 H) 4.30-4.37 (m, 1 H) 3.72 (s, 3 H) 1.99-2.03 (m, 2H) 1.47-1.85 (m, 6 H). m/z (ESI) 516.0 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:14]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:23]([CH2:26][C:27](=[O:29])[CH3:28])(=[O:25])[CH3:24]>C(O)(=O)C.Cl.O.C(O)C>[N:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][N:14]=[C:26]([C:27](=[O:29])[CH3:28])[C:23](=[O:25])[CH3:24])=[CH:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(N2CCOCC2)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of 4-morpholin-4-ylaniline (1000 mg, 5.62 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (465 mg, 6.74 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2764 mg, 33.71 mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(4-morpholin-4-ylphenyl)hydrazono]pentane-2,4-dione (900 mg, 55%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([NH:35][CH3:36])[CH:22]=1)[OH:20].CO.C(Cl)(Cl)Cl>CO.[Pd]>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:35][CH3:36])[CH:22]=1)[OH:20]
Reactant: CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 26 (in a solution of 200 mg of the compound in 25 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (100 mg), whereby the above-identified compound (153 mg) was obtained. Rf=0.09 (methanol/chloroform of 1/10).
Reaction SMILES: [C:1]1([C:7]2(C=O)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:48]([O-])([O-])=O.[K+].[K+].O1CCOC1>C(Cl)Cl.COCCOCCN(CCOCCOC)CCOCCOC.O>[C:1]1([C:7]2([CH:48]=[CH:28][CH:24]3[O:23][CH2:27][CH2:26][O:25]3)[C:19]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]3[C:8]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCO1
Solvent: O
Product: C(=CC1(c2ccccc2)c2ccccc2-c2ccccc21)C1OCCO1
Reaction time: 15 h

Procedure:
9-Phenyl-9-fluorene carboxaldehyde is dissolved in CH2Cl2 with TDA-1 {tris[2-(2-methoxyethoxy)ethyl]amine} (1 eq). 1,3-dioxolan-2-ylmethyltriphenylphosphonium bromide (1.1 eq) is added followed by a solution of sat. aq K2CO3. The mixture is warmed to reflux and stirred for 15 h. The reaction mixture is diluted with H2O and the resulting mixture is extracted with CH2Cl2. The organic layer is washed consecutively with H2O, 2% aq HCl, and H2O, dried (Na2SO4), and concentrated in vacuo. Purification by liquid chromatography on silica gel affords an E/Z mixture of the dioxolane.
Reaction SMILES: [CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH:5]2[CH2:6][C:7](=O)[CH2:8]3)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH:5]2[CH2:6][C:7](=[N:20][OH:21])[CH2:8]3)[CH2:3][CH2:2]1
Reactant: O=C1CC2CCC(C1)N2C1CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC2CCC(C1)N2C1CC1
Temperature: 23 °C
Yield: 84 %

Procedure:
A mixture of 8-cyclopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS no: 60206-33-9) (17.86 g, 108.08 mmol) in ethanol (500 mL) with pyridine (13.05 mL, 162.1 mmol) and hydroxylamine hydrochloride (9.764 g, 140.51 mmol) was refluxed overnight. Cooled to 23° C., filtered off, washed with ethanol and ether and dried in vacuum to give a white solid, which was suspended in 200 mL sat. Na2CO3 solution and extracted 3 times with dichloromethane, the combined organic layers were dried over Na2SO4, filtered off and evaporated totally, dried in high vacuum to give the title compound as white crystals (16.3 g, 84%); MS: m/e=181.2 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([CH3:10])[CH3:9].[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([CH:29]=[CH:30][C:31]3[CH:32]=[C:33]([CH:37]([OH:41])[CH2:38][CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([CH:29]=[CH:30][C:31]3[CH:32]=[C:33]([C:37](=[O:41])[CH2:38][CH2:39][CH2:40][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:8]([O:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)([CH3:10])[CH3:9])[CH:34]=[CH:35][CH:36]=3)=[N:26]2)=[CH:21][CH:20]=1.[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([CH:29]=[CH:30][C:31]3[CH:32]=[C:33]([C:37](=[O:41])[CH2:38][CH2:39][CH2:40][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:8]([OH:11])([CH3:9])[CH3:10])[CH:34]=[CH:35][CH:36]=3)=[N:26]2)=[CH:21][CH:20]=1
Reactant: C=CCC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1I
Product: CC(C)(O)c1ccccc1CCCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Product: CC(C)(OC1CCCCO1)c1ccccc1CCCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
Using the procedure of Example 80, Step 2, the iodide of Step 2 (2.69 g, 7.78 mmol) was coupled with the homoallylic alcohol of Step 1 (2.11 g, 7.0 mmol) at 100° C. for 4 hours to afford 1.50 g of the title compound and 1.04 g of 2-(2-(4-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-4-oxobutyl)phenyl)-2-propanol, which can be converted to the title product using the procedure of Step 2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cn1cccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2cccn2C)cc1
Reaction time: 0.75 h
Yield: 28.5 %

Procedure:
A solution of 5 g (0.06 mole) N-methylpyrrole and 13.3 g (0.078 mole) of 4-methoxybenzoyl chloride in 50 mL of dry toluene was heated under reflux overnight with an argon stream bubbling through the reaction mixture. After cooling, 40 mL of 20% 3-dimethylaminopropylamine in H2O was added and the mixture stirred for 45 minutes. Diethyl ether was added and the organic solution was washed with 1N HCl, NaHCO3, water, brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from ethanol to give 3.68 g of product: mp. 66-68° C.; mass spectrum (CH4—Cl) m/z=216 (M+1); NMR (CDCl3) d 7.85 (d, 2 H); 6.9-7.1 (d,s, 3 H); 6.7 (d, 1 H); 6.15 (d, 1 H); 4.1 (s, 3 H); 3.9 (s, 3 H). Anal Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.59; H, 6.06; N, 6.43.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[Cl:29].Br[CH2:31]C1C=CC=C(Cl)C=1Cl>>[Cl:29][C:20]1[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[CH:13]([CH3:31])[CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Reactant: Clc1cccc(CBr)c1Cl
Product: CC1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Yield: 63 %

Procedure:
Example 14 was made in a manner analogous to Example 2 substituting Intermediate 3 for Intermediate 1 and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene for 1-(bromomethyl)-2,3-dichlorobenzene to provide the desired compound as a white solid (102 mg, 63%). MS (ESI): mass calcd. for C18H14ClF3N6O, 422.1; m/z found, 423.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 89.48 (d, J=1.2 Hz, 1H), 8.84-8.82 (m, 2H), 7.85-7.82 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 5.20 (d, J=16.5 Hz, 1H), 4.98 (dd, J=13.8, 2.2 Hz, 1H), 4.80 (dd, J=13.8, 4.6 Hz, 1H), 4.56 (d, J=16.6 Hz, 1H), 4.23-4.10 (m, 1H), 1.23 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl.C(O)(=O)CCC(O)=O>N1C=CC=CC=1.O>[C:12]([C:11]1[CH:10]=[C:9]([N:8]([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=2)[C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:17]=[CH:16][CH:15]=1)([OH:14])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: O=C(O)CCC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 150 °C
Yield: 47.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3.0 g (0.0088 mole) of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid and 9.0 g (0.090 mole) of succinic anhydride was heated at 150° C. for 15 minutes. The reaction mixture was diluted with pyridine (50 ml) and water, and was poured into cold dilute hydrochloric acid. The resulting precipitate was recrystallized from a mixture of 14 ml of ethanol and 22 ml of water to give a white solid. This solid was heated in 70 ml of water to dissolve any succinic acid, and was collected and heated in 40 ml of ethyl acetate. The ethyl acetate solution was filtered to remove a small amount of insoluble material. The ethyl acetate filtrate was concentrated to 20 ml, and was then diluted with 10 ml of hexane. The resulting precipitate was collected and dried to give 1.85 g of white solid N-(3-carboxyphenyl)-N-(3,5-di-t-butyl-4-hydroxyphenyl)succinamic acid, m.p. 182°-183° C. Analysis: Calculated for C25H31NO6 : % C, 68.0; % H, 7.1; % N, 3.2; Found: % C, 68.2; % H, 7.1; % N, 3.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: C#CCCCCCl
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C#CCCCCCl)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 65.5 %

Procedure:
Following the general procedure using 4-bromoanisole (60 mg, 0.48 mmol) and 6-chloro-1-hexyne (90 μL, 0.74 mmol), the reaction was stirred for 25 h at rt. Column chromatography on silica gel (eluting with 1% EtOAc/hexanes) afforded the product as a pale yellow oil (70 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:15]2[CH:16]=[C:17]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:18]=[CH:19][C:14]=2[O:13][CH:12]=1)[C:5]([OH:7])=O.[CH3:26][NH2:27].O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:15]2[CH:16]=[C:17]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:18]=[CH:19][C:14]=2[O:13][CH:12]=1)[C:5]([NH:27][CH3:26])=[O:7]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)cc4Cl)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)c(Cl)c1
Yield: 21 %

Procedure:
In the same manner as in Example 117 and using 3-chloro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and using 2M methylamine-tetrahydrofuran solution instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 21%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.CO[C:15](OC)([N:17]([CH3:19])[CH3:18])[CH3:16]>C(Cl)(Cl)Cl>[CH3:19][N:17]([CH3:18])/[C:15](/[CH3:16])=[C:8](/[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1)\[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: COC(C)(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: C/C(=C(/C#N)C(=O)c1ccc(F)cc1)N(C)C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 1.6 g. of p-fluorobenzoylacetonitrile [Pihl et al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Univ., 5 (1), 27, (1968)] in 30 ml. of chloroform, cooled to -10° C., is added 1.4 g. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at -10° C. for 2 hours and the evaporated in vacuo to an oil. This oil is dissolved in 150 ml. of benzene and filtered through magnesol. The filtrate is evaporated to 50 ml. and petroleum ether is added to effect crystallization. The product is collected by filtration and then recrystallized from benzene-petroleum ether with charcoal treatment giving the desired product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:50]=[C:51]([CH2:56][CH:57]([C:59]2[N:60]=[CH:61][S:62][C:63]=2[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[CH3:70])[NH2:58])[CH:52]=[C:53]([F:55])[CH:54]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[C:51]([CH2:56][CH:57]([NH:58][C:36](=[O:38])[CH2:35][C:29]2[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([OH:25])[CH:27]=3)[NH:31][CH:30]=2)[C:59]2[N:60]=[CH:61][S:62][C:63]=2[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[CH3:70])[CH:52]=[C:53]([F:55])[CH:54]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: Cc1ccccc1-c1scnc1C(N)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1scnc1C(Cc1cc(F)cc(F)c1)NC(=O)Cc1c[nH]c2ccc(O)cc12
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 13D (33.1 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.18 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.35-7.15 (m, 2H), 7.05 (t, J=7.1 Hz, 2H), 6.94 (dd, J=10.2, 5.8 Hz, 2H), 6.75 (t, J=7.2 Hz, 2H), 6.59-6.35 (m, 3H), 3.38 (s, 2H), 3.01 (d, J=7.5 Hz, 2H), 1.81 (s, 3H). MS (m/z) 504 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[S:15]>C(#N)C>[F:10][C:11]([F:17])([F:16])[CH2:12][NH:13][C:14](=[S:15])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: CSc1nccc(N)n1
Solvent: CC#N
Product: CSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 51.2 %

Procedure:
A mixture of 4-amino-2-methylthiopyrimidine (2.1 g.), 2,2,2-trifluoroethylisothiocyanate (2.8 g.) and acetonitrile (5 ml.) was stirred at 70° for 72 hours and then cooled, and the solid that crystallised was collected to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:33])[CH3:32])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(C(C)=O)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(C)=O)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 2-(4-acetylbenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[C:9]([C:25]([NH2:27])=[O:26])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:12](Cl)[N:13]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>O.O1CCOCC1.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>[NH2:7][C:8]1[C:9]([C:25]([NH2:27])=[O:26])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:12]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)[N:13]=1
Reactant: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Reactant: OB(O)c1cccs1
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: C1COCCO1
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2cccs2)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (138 mg) in water (0.8 ml) was added to a suspension of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (100 mg), 2-thienylboronic acid (104 mg) and tetrakis(triphenylphosphine)palladium (11.3 mg) in dioxane (2 ml) and the mixture was stirred at 100-105° C. for 4 hours. After addition of water (10 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-(2-thienyl)-2-pyrazinecarboxamide as a solid (85 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6]
Reactant: CC(CCCO)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(CCCBr)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To an ice-cold solution of tert-butyl (5-hydroxypentan-2-yl)carbamate (3.6 g, 17.71 mmol) in dichloromethane (150 mL) was added triphenylphosphine (6.97 g, 26.6 mmol) followed by carbon tetrabromide (8.81 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica) using 2-5% ethyl acetate in pet-ether to give tert-butyl (5-bromopentan-2-yl)carbamate (2.5 g, 53%) as a light brown liquid. 1H NMR: (400 MHz, CDCl3) δ ppm 4.29 (1H, br s), 3.68 (1H, br s), 3.42 (2H, t, J=6.8 Hz), 1.94-1.86 (2H, m), 1.59-1.46 (2H, m), 1.44 (9H, s), 1.13 (3H, d, J=6.4 Hz).
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]3[N:15]=[CH:16][NH:17][C:18](=[O:19])[C:13]=3[CH:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O[C:24](=[O:26])[CH3:25])(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:2]([O:3][C@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:24](=[O:26])[CH3:25])[O:7][C@H:1]1[N:10]1[C:14]2[N:15]=[CH:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]cnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(=O)[nH]cnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 3.0 g of 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one, eight ml of acetic anhydride, 150 ml of pyridine, and 50 mg of p-dimethylaminopyridine is stirred at room temperature for 24 hours, evaporated in vacuo, co-evaporated with xylenes, and distributed between ethyl acetate and water. The ethyl acetate layer is washed with saturated NaHCO3 and dried with MgSO4. Removal of the ethyl acetate provides 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. This is dissolved in 150 ml of dry pyridine, treated with 8.8 g of phosphorus pentasulfide, and heated under reflux for 5 hours. The pyridine is removed in vacuo and the residue is treated with water. The precipitate is filtered, washed with water, and recrystallized from ethanol to afford 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo-[2,3-d]pyrimidine-4-thione. A solution of 5.0 g of 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-4-thione, 200 ml of methanol, and 54 mg of sodium methalate is heated under reflux for 2 hours and treated with IRC-50 ion exchange resin. The filtrate is evaporated in vacuo and the resulting residue is recrystallized from ethanol-water to provide 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidine-4-thione.