Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.CCO.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(F)ccc1N
Reaction time: 96 h
Yield: 97.7 %

Procedure:
A round-bottom flask was charged with 4-fluoro-2-isopropoxy-1-nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10% Pd/C (50% in water, Degussa type E101; 10 g, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 4 d using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98%) as a brown liquid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 6.67-6.72 (dd, 1H, J=2.7 Hz, 11 Hz), 6.55-6.60 (dd, 1H, J=6.0 Hz, 8.7 Hz), 6.43-6.49 (td, 1H, J=2.7 Hz, 8.4 Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −127.4 (sextet); m/z=170 (M+H)+.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].[OH-:17].[Na+]>O>[C:12]([NH:10][C:8](=[N:9][C:12]([O:14][CH2:15][CH3:16])=[O:17])[S:7][CH3:6])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: [OH-]
Reactant: CSC(=N)N
Reactant: CCOC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N=C(NC(=O)OCC)SC
Reaction time: 0.08 h
Yield: 88 %

Procedure:
2-Methyl-2-thiopseudourea sulfate (15 g; 53.9 mmol; 1 eq) was suspended in 20 mL of water and cooled to 0°-5° C. Ethyl chloroformate (29.2 g, 269 mmol; 5 eq) was added and the mixture was stirred for 5 minutes. Sodium hydroxide solution (25% w/w) was added drop-wise until the pH reached 8 (by pH paper). The white solid was collected by filtration and air dried to give 1,3-dicarboethoxy-2-methyl-2-thiopseudourea (22.2 g, 88%) as a white solid, mp 42°-44° C. A small portion was dried in vacuo for analysis.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[C:11]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[F-].[Cs+]>C(COC)OC.C(Cl)Cl.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>[C:16]([N:9]1[C:5]2[NH:6][C:7](=[O:8])[C:2]([C:23]3[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=3)=[CH:3][C:4]=2[C:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:10]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)n1nc(C2CCC2)c2cc(Br)c(=O)[nH]c21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)n1nc(C2CCC2)c2cc(-c3cc(Cl)cc(Cl)c3)c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
To a stirring solution of 5-bromo-1-tert-butyl-3-cyclobutyl-1,7-dihydro -pyrazolo[3,4-b]pyridin-6-one (50.0 mg, 0.15 mmol) in dimethoxyethane (1.5 mL) was added 3,5-dichlorophenyl-boronic acid (32.6 mg, 0.17 mmol), followed by cesium fluoride (51.9 mg, 0.34 mmol), and Pd(PPh3)4 (catalytic amount, 0.005 mmol). The reaction mixture was heated to reflux. After 3 hr, additional amounts of 3,5-dichlorophenyl-boronic acid (32.6 mg, 0.17 mmol), cesium fluoride (51.9 mg, 0.34 mmol), and Pd(PPh3)4 (catalytic amount, 0.005 mmol) were added. After a total of 18 hr, the reaction was cooled to room temperature, diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography with a Biotage® column, eluting with 5% EtOAc/toluene. The product-containing fractions were collected and concentrated to give the title compound (7.0 mg, 12% yield). LRMS m/z (APCl) 390. 392(M+1).
Reaction SMILES: N.C([O:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[CH3:30])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.[Cl:31]C(Cl)Cl>CO>[ClH:31].[OH:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[CH3:30])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(C)c(OC(C)=O)c3)c2cc1OC
Reactant: ClC(Cl)Cl
Agent: N
Solvent: CO
Product: COCCOc1cc2ncnc(Nc3ccc(C)c(O)c3)c2cc1OC
Product: Cl
Yield: 80 %

Procedure:
Concentrated aqueous ammonia (8 ml) was added to a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline (2.38 g, 6 mmol) in a mixture of trichloromethane (24 ml) and methanol (24 ml). The mixture was heated at reflux for 8 hours and the volatiles removed by evaporation. The residue was triturated with water, the resulting solid was collected by filtration and recrystallised from methylene chloride/ethanol. The product was redissolved in a mixture of methylene chloride/ethanol and a saturated solution of hydrogen chloride in ethanol was added. The solvent was partially removed by evaporation and the mixture cooled. The resulting precipitate was collected by filtration washed with ether and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (1.68 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+]>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[O:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OC[C@@H](c2cc(F)cc(F)c2)NC1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)(C)OC[C@H]1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (5R)-5-(3,5-difluorophenyl)-2,2-dimethylmorpholin-3-one from Step G (150 mg, 0.62 mmol) in DMF (2 mL) at 0° C. was added NaH (27 mg of a 60% dispersion in oil, 0.68 mmol). After 10 min, ethyl bromoacetate (104 mg, 0.62 mmol) was added and the mixture was stirred at 0° C. for 30 min. Saturated aqueous NaHCO3 (5 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 70:30, to give the title compound. MS: m/z=328 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[CH:6]=[CH:5]2.C[N:15](C=O)C.CC#N.C1(=O)NC(=O)C2=CC=CC=C12.[K].NN>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:15])[CH:6]=[CH:5]2
Reactant: ClCc1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CC#N
Product: NCc1ccc2cc(Br)ccc2n1
Temperature: 60 °C

Procedure:
To 4a (440 mg, 1.7 mmol) in 1:1 DMF/MeCN (3 mL) at room temperature was added potassium phthalimide (350 mg, 1.9 mmol), and the reaction was heated to 60° C. overnight. The mixture was poured into water and filtered, and the solid was suspended in EtOH (10 mL). Hydrazine (82 mg, 2.5 mmol) was added, and the mixture was heated to 70° C. for 30 minutes. The reaction was then concentrated, and the crude material, 4b, was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Brc1ccc(-c2nc[nH]c2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(Br)cc2)c1-c1ccc(Br)cc1
Yield: 71.2 %

Procedure:
4,5-Di-(4-bromophenyl)imidazole (2.13 g) was treated with ethyl 8-bromooctanoate (2 g) and K2CO3 (0.5 g) in 2-butanone as described in Example 9 to give ethyl 8-(4,5-di-(4-bromophenyl)imidazol-1-yl)-octanoate (2.2 g, 52%) as a pale yellow oil.; Found: C, 55.13; H, 5.19; N, 5.18; Br; 28.76%; C28H28Br2N2O2 requires: C, 54.76; H, 5.15; N, 5.11; Br, 29.15%
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH2:8][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=1
Reactant: Clc1ncc(CBr)cc1Br
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncc(Cn2ccnc2)cc1Br

Procedure:
Synthesized from 6a (2.38 g, 8.34 mmol), imidazole (1.14 g, 16.7 mmol) and K2CO3 (5.76 g, 41.7 mmol) according to Method B. Yield: 1.88 g, 6.90 mmol, 83%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.14 (s, 2H), 6.89 (bs, 1H), 7.13 (d, J=4.0 Hz, 1H), 7.61-7.63 (m, 1H), 7.70 (brs, 1H), 8.20 (brs, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=46.8, 118.9, 120.8, 130.5, 132.2, 137.2, 140.8, 146.3, 150.9; MS (ESI): m/z=272.05 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:15](=O)([O-])[O-].[K+].[K+].[C:21](O)(=O)[C:22](O)=O>C(#N)C>[CH2:15]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH:21]=[CH2:22]
Reactant: O=C(O)C(=O)O
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.15 g, 0.75 mmol), acetonitrile (6 mL), potassium carbonate (0.208 g, 1.5 mmol) allyl bromide (0.065 mL, 0.76 mmol). Flash chromatography on silica gel (Ethyl acetate/methanol, 10:1). Yield 0.1 g. [α]D=+23.4°; The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether; M.p. 119-120° C.; MS m/z (relative intensity, 70 eV) 239 (M+, 13), 83 (bp), 141 (41), 82 (39), 198 (35), 84 (32).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:35](=[O:38])[CH2:36][CH3:37])[CH2:3][C@H:4]4[F:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Reactant: CCC(=O)Cl
Product: CCC(=O)N[C@H]1C[C@@H](F)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f71) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>C(O)(=O)C>[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[N:15]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(F)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
A solution of 5 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated with 4.3 parts of 2,4-difluoroaniline at once and stirred for one hour. After refluxing for 20 hours, the reaction mixture was poured over 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40°C to yield 5 parts off-white crystals of 2-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 73°-74°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.Cl.[CH3:14]O>O1CCOCC1>[CH3:14][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: CO
Reactant: O=C(O)Cc1cc(Br)ccc1F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(Br)ccc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-2-fluoro-phenyl)-acetic acid (2.3 mmol) in MeOH (15 mL) was added 4N HCl in 1,4-dioxane (2 mL), and the reaction was stirred at 90° C. for 2 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2>>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH:15]=[CH:14]2
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 4-fluorobenzyl bromide and 5-bromoindole in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a white solid; mp: 57-58° C. Mass spectrum (APCI, [M+H]+) m/z 304. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (d, 1H J=1.8 Hz), 7.55 (d, 1H, J=3.2 Hz), 7.43 (d, 1H, J=8.9 Hz), 7.24-7.19 (m, 3H), 7.12 (t, 2H, J=8.9 Hz), 6.47 (d, 1H, J=3.6 Hz), 5.40 (s, 2H), and 2.22 ppm (s, 3H). Elemental Analysis for C15H11BrFN: Calculated: C, 59.23; H, 3.65; N, 4.61. Found: C, 59.00; H, 3.55; N, 4.58.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:64][C:65]1[CH:72]=[CH:71][C:68]([CH2:69][NH2:70])=[CH:67][CH:66]=1>CN(C)C=O>[Cl:64][C:65]1[CH:72]=[CH:71][C:68]([CH2:69][N:70]2[C:16](=[O:18])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]2([C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)[OH:13])=[CH:67][CH:66]=1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: NCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1COc2ccc(C3(O)c4ccccc4C(=O)N3Cc3ccc(Cl)cc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
To a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)carbonylbenzoic acid (50 mg, 0.17 mmol) in N,N-dimethylformamide (1.00 mL) was added N-methylmorpholine (74 uL, 0.67 mmol) followed by addition of HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.34 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of 4-chloro-benzylamine (49 uL, 0.40 mmol). The reaction mixture was then heated to 60° C. for 2 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with brine, 1.0 M aq. hydrochloric acid, brine, saturated aq. sodium-hydrogencarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was recrystallized from methanol to afford the title compound (7.3 mg, 15%). MS (EI) for C22H15ClN2O4: 443 (MNa+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)=[O:22].O>C(Cl)(Cl)Cl.N1CCCCC1>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([NH:23][C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:22])[CH:25]=1
Reactant: COCCOC(=O)Nc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: COCCOC(=O)Nc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
In 10 ml of chloroform were dissolved 2.04 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 2.23 g of 3-[(2-methoxyethoxy)carbonylamino]benzaldehyde and 60 mg of piperidine, and the solution was heated under refluxing for 1 hour and 30 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and fractions corresponding to Rf=0.3 were collected by thin layer chromatography (silica gel, hexane/acetone (1:1)), and concentrated to obtain 3.42 g of 4-hydroxy-3-[3-[3-[(2-methoxyethoxy)carbonylamino]phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (24d)].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na]>CN(C=O)C>[CH2:11]([NH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nnccc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(O)c1ccnnc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.9 %

Procedure:
3-Aminopyridazine-4-carboxylic acid (200 mg, 1.43 mmol) and benzaldehyde (0.18 mL, 1.73 mmol) were stirred in DMF (3 mL) at 90° C. for four days. The reaction mixture was allowed to cool to rt and sodium triacetoborohydride (605 mg, 2.86 mmol) was added. The reaction was stirred for 16 h. The reaction was quenched with water and extracted with EtOAc. The extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography (0-20% MeOH/DCM). The relevant fractions were concentrated to give 6.3 mg (4%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.51 (d, 1H, 5 Hz), 7.63 (d, 1H, J=5.0 Hz), 7.30-7.39 (m, 4H), 7.22-7.25 (m, 1H), 4.72 (br s, 2H). [M+H] calc'd for C12H11N3O2, 230. found 230.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH3:14])=[CH:8][N+:7]=1[O-:15].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([O:13][CH3:14])=[CH:8][N+:7]=1[O-:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C)c(Cl)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1c[n+]([O-])c(Cl)c(C)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
Concentrated nitric acid (2.5 mL) was added drop-wise to a 0° C. solution of C2 (350 mg, 2.02 mmol) in concentrated sulfuric acid (2.5 mL). The reaction mixture was heated at 90° C. for 1 hour, then cooled to room temperature and poured onto crushed ice. The resulting mixture was neutralized to pH 6-7 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the product as a light yellow solid. Yield: 370 mg, 1.69 mmol, 84%. LCMS m/z 219.0, 221.1 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 3.94 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: N#C[Cu]
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(F)c1
Yield: 101.4 %

Procedure:
2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in 20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalytic amount of CuI (200 mg). The slurry was refluxed for 1 hour. Diluted with EtOAc. Filtered through celite. Concentrated in vacuuo to yield solid 4-amino-3-fluorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)+ 137.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.Cl.[N:12]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:8][N:6]1[C:5](=[O:9])[NH:4][C:3](=[O:10])[C:2]([N:15]2[CH2:16][CH2:17][N:12]([C:18](=[O:19])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])[CH2:13][CH2:14]2)=[N:7]1.[C:20]1([CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: Cn1nc(Br)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1ccccc1
Product: Cn1nc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)c(=O)[nH]c1=O
Yield: 25 %

Procedure:
The compound 2 (yellow powder) is prepared from the triazine 2e and from the intermediate 6a according to the synthesis method 1 in toluene (yield: 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:14](Cl)=[O:15])=[N:11][C:10]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[NH3:11].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:14]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:15])=[N:11][C:10]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(Cl)c2)[nH]1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N
Product: O=C(c1nc(-c2ccncc2)c(-c2ccc(Cl)c(Cl)c2)[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
The product of Step 1 (52 mg, 0.15 mmol) was dissolved in anhydrous dichloromethane (3 ml), piperidine (0.025 ml, 0.23 mmol) was added followed by triethylamine (0.084 ml, 0.6 mmol) and the mixture stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 5% of a 9:1 methanol:0.880 ammonia solution, in dichloromethane to give the title compound as a white solid (16 mg, 26%); MS(AP+) m/e 402 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].C(N(CC)CC)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Temperature: 50 °C
Yield: 77.2 %

Procedure:
A mixture of Intermediate 1 (2.5 g), ethynylbenzene (800 mg), copper (I) iodide (124 mg), bis(triphenylphosphine)palladium (II) dichloride (1.37 g), triethylamine (19.0 g) and acetonitrile (20 ml) is heated with stirring at 50° C. under argon atmosphere. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (1.8 g).