Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:23][O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[N:21][N:22]=2)[N:19]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34]([C:25]([O:24][CH2:23][C:20]3[N:18]4[N:19]=[C:14]([C:6]5[CH:5]=[CH:4][C:3]([N:2]([CH3:12])[CH3:1])=[N:8][CH:7]=5)[CH:15]=[CH:16][C:17]4=[N:22][N:21]=3)=[CH:26][CH:27]=[N:28]2)=[CH:33][CH:32]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N(C)C)nc5)nn34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A 48 mL tube was charged with 6-(dimethylamino)pyridin-3-ylboronic acid (0.109 g, 0.658 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), and DMF (3.00 ml, 38.6 mmol), and stirred for 10 minutes. A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, and heated in a 80° C. oil bath for 5 hours. The mixture was concentrated, and the residue was triturated with water to give a brown solid which was purified by MPLC using a 40 g column, eluting with 1-5% MeOH/DCM over 40 minutes to give 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine as a dark green solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21]([OH:23])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:39][N:40]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Si:31]([O:30][CH2:29][C@H:28]([CH3:38])[O:27][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:26]=1)[C:21]([NH:45][C:42]1[CH:43]=[CH:44][N:40]([CH3:39])[N:41]=1)=[O:23])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
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: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
DIPEA (4.06 g, 23.4 mmol) was added to a suspension of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (2.43 g, 5.84 mmol), 1-methyl-1H-pyrazole-3-amine (0.85 g, 8.76 mmol) and HATU (4.66 g, 12.3 mmol) in DMF (50 mL) and stirred at ambient temperature for 16 hours. The resultant mixture was partially reduced in vacuo, poured onto water (100 mL) and extracted with diethyl ether (2×50 mL). The extracts were washed with water and brine then dried (MgSO4), filtered and reduced to an opaque gum which partially crystallized. The crude product was purified by column chromatography, eluting with 0-100% ethyl acetate in isohexane, to give the title compound as a colourless oil (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(C)c3)CC2)ccc1Cl
Yield: 56 %

Procedure:
The title compound (22 mg, 56%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methylbenzoyl chloride. MS:387.4 (MH+)
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([S:9][CH3:10])([CH3:8])[CH:5]=[N:6][OH:7].[CH3:11][N:12]([S:16][N:17]([CH3:19])[CH3:18])[C:13](F)=[O:14]>C1C=CC=CC=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>[CH3:11][N:12]([S:16][N:17]([CH3:19])[CH3:18])[C:13]([O:7][N:6]=[CH:5][C:4]([CH3:8])([S:9][CH3:10])[CH3:3])=[O:14]
Reactant: CN(C)SN(C)C(=O)F
Reactant: CSC(C)(C)C=NO
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CSC(C)(C)C=NOC(=O)N(C)SN(C)C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of 3.3 g powdered potassium hydroxide, 0.1 g dicyclohexyl-18-crown-6, and 6.7 g (0.05 mole) of 2-methyl-2-(methylthio)propionaldehyde oxime in 200 ml of benzene was stirred 1 hr. at room temperature. N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride (8.0 g, 0.05 mole) was then added, and the mixture was stirred overnight at room temperature. The solution was extracted three times with water, dried (MgSO4), and concentrated in vacuo. The oily residue was recrystallized from n-hexane to give 10 g (75.5 percent yield) of 2-methyl-2-(methylthio)propionaldehyde O-[N-methyl-N-(dimethylaminosulfenyl)carbamoyl]oxime, m.p. 48°-50° C.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH:12](C)[C:13](Cl)=O.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:12]([CH3:13])=[CH:9][C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CC(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)=Cc1ccc([N+](=O)[O-])o1
Reaction time: 0.67 h

Procedure:
To a solution of 9 g of 5-nitro-2-furaldehyde and 11.0 g of 2-chloropropionyl chloride in 100 ml of benzene was added dropwise at 25°-30° over a 20-minute period a solution of 10 g of triethylamine in 30 ml of benzene. After an additional 40 minutes, the mixture was stirred at reflux for 1.5 hours. The cooled mixture was washed with water, dried and concentrated under reduced pressure to leave a residue which was distilled to give a liquid product, b.p.: 92°-100° at 0.15 torr. This product was triturated with n-hexane to give 3 as a mixture of stereisomers, a tan solid, m.p.: 55°-65°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)OCC)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 677.4 %

Procedure:
To a 0° C. solution of 4-bromophenol (1.87 g, 1.08 mmol), ethyl 4-(1-hydroxybutyl)benzoate (2 g, 0.9 mmol) and triphenylphosphine (2.83 g, 1.08 mmol) in THF (20 mL) was added DIAD (2.18 g, 1.08 mmol). The resulting mixture was stirred at 30° C. overnight. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (3*25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (+/−)-ethyl 4-(1-(4-bromophenoxy)butyl)benzoate (2.3 g, 67.7%) as a yellow oil. 1HNMR (400 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.8 Hz, 2H), 5.08 (m, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.98-1.94 (m, 1H), 1.80-1.74 (m, 1H), 1.52-1.50 (m, 1H), 1.43-1.39 (m, 1H), 1.37 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[C:24]([Cl:29])=[N:25][CH:26]=[CH:27][CH:28]=1>>[Cl:29][C:24]1[C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Clc1ncccc1Br
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cccnc2Cl)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 3-bromo-2-chloro-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:57][CH2:58][CH2:59][N:60]1[CH2:64][CH2:63][CH:62]([NH:65][C:66](=[O:68])[CH3:67])[CH2:61]1>CN(C=O)C>[C:66]([NH:65][CH:62]1[CH2:63][CH2:64][N:60]([CH2:59][CH2:58][NH:57][C:31](=[O:33])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:61]1)(=[O:68])[CH3:67]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: CC(=O)NC1CCN(CCN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (260 mg, 0.5 mmol) in DMF (3 mL) was added HOBt (101 mg, 1.5 eq.), EDAC.HCl (144 mg, 3 eq.) and TEA (152 mg, 1.5 eq.). After stirring at rt for 30 mins, to the mixture was added N-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (128 mg, 1.5 eq.). After stirring at 40° C. for overnight, the cooled reaction was concentrated and the residue was purified on a silica gel column to give the title compound as a yellow solid.
Reaction SMILES: [NH:1]([CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].C([O-])(=O)C.[NH4+]>>[C:17]([C:19]1[C:20](=[O:21])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:18]
Reactant: O=C(CNc1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#CC1=C(c2ccccc2)CN(c2ccccc2)C1=O
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A mixture of 21.1 grams (0.1 mol) of 2-anilinoacetophenone, 31.8 grams (0.28 mol) of ethyl cyanoacetate, and 8 grams (0.13 mol) of ammonium acetate were placed in a reaction flask fitted with a distillation head. The reaction mixture was placed in an oil bath pre-heated to a temperature of 180° C. At a reaction temperature of 100° C. the solid mixture liquified and stirred easily. The internal temperature of the reaction rose to 150° C. over a period of 30 minutes while a colorless distillate was removed. After 30 minutes no further distillate was collected and the product mixture was cooled. To the dark homogeneous liquid product was added 40 mL of absolute ethanol with stirring. The precipitated yellow crystalline product was collected by filtration and washed with 3×10 mL ethanol, 2×25 mL ligroin, and air dried to afford 10.05 grams of crude product. Recrystallization from 80 mL of acetonitrile gave 9.1 grams (35 mmol, 35 % yield) of 3-cyano -1,4-diphenyl-3-pyrrolin-2-one as yellow crystals, m. p.=188°-190° C. Elemental Analysis: Calculated: C=78.44, H=4.65, N=10.76; Found: C=78.36, H=4.90, N=10.81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[C:10]=2[C:9]1=[O:30].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[C:10]=2[C:9]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(CO)n(-c3ccccc3Cl)c(=O)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A mixture of 2-(5-(2-chlorophenyl)-6-(hydroxymethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1H-isoindole-1,3(2H)-dione obtained in Step I (317 mg), Dess-Martin periodinane (351 mg) and dichloromethane (7.53 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. to give the title compound (311 mg).
Reaction SMILES: [CH2:1]=O.[NH2:3][CH2:4][C@@:5]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([OH:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1C=CC=CC=1>[Si:9]([O:8][CH2:7][CH2:6][C@:5]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:16][CH2:1][NH:3][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@](O)(CN)c1ccc(F)cc1
Reactant: C=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC[C@@]1(c2ccc(F)cc2)CNCO1
Yield: 104.2 %

Procedure:
Paraformaldehyde (18.50 g, 0.617 mol) was added to a solution of (2R)-1-amino-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)butan-2-ol (128.92 g, 0.411 mol) in benzene (1000 mL), a water separator was mounted, and the mixture was stirred at reflux temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 139.43 g of crude (5R)-5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(4-fluorophenyl)-1,3-oxazolidine as a brown oily substance.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:61]([C:68]1[CH:69]=[C:70]([CH:74]=[CH:75][CH:76]=1)[C:71](O)=[O:72])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:71](=[O:72])[C:70]1[CH:74]=[CH:75][CH:76]=[C:68]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:69]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 72 %

Procedure:
DIPEA (73 mg, 0.097 mL, 0.56 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (96 mg, 0.22 mmol) in DMF (1 mL). HOBT (30 mg, 0.22 mmol) and EDCI.HCl (43 mg, 0.22 mmol) were then added at room temperature. After 2 minutes, 3-phenoxybenzoic acid (40 mg, 0.19 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 70 mg (72.5% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-3-phenoxy-benzamide. LCMS Purity: 89.64%. 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 7.9-7.4 (m, 8H), 7.2 (m, 1H), 7.1-7.0 (d, 1H), 4.2-4.0 (m, 2H), 3.8-3.4 (m, 6H), 3.3-3.2 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.Br[C:38]1[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C([O-])(O)=O.[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=3)[C:43]([N:45]([CH3:46])[CH3:47])=[O:44])[CH:16]=2)[NH:11][CH:10]=1
Reactant: CN(C)C(=O)c1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)N(C)C)c3)cc12
Yield: 56.7 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.136 g, 0.270 mmol), 5-Bromo-N,N-dimethyl-nicotinamide (0.0756 g, 0.332 mmol; preparation described below), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)-dichloride dichloromethane adduct (16.2 mg, 0.01 mmol), acetonitrile (2 mL) and saturated aqueous NaHCO3 (2 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 3:1 MeOH/acetone (4 mL total) and treated with 500 μL of 50% w/w KOH(aq) for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was partitioned between EtOAc and water, then the layers were separated, and the organic phase was washed 2× with water. The organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexanes afforded the title compound as a tan powder (57 mg, 57%). 1H-NMR (500 MHz, d6-DMSO) δ=11.96 (br. s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H), 7.59 (dd, J=2.0, 5.5 Hz, 1H), 7.25 (dd, J=1, 7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 3.76 (s, 3H), 2.97 (s, 3H), 2.92 (s, 3H); MS: m/z 373.1 [MH+].
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]1[S:27][C:26](=[O:28])[NH:25][CH:24]1[C:29]([OH:31])=O.[N+]([O-])(O)=O.[N+:36]([O:39][CH2:40][CH2:41][NH2:42])([O-:38])=[O:37]>O1CCCC1>[N+:36]([O:39][CH2:40][CH2:41][NH:42][C:29]([CH:24]1[CH:23]([C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)[S:27][C:26](=[O:28])[NH:25]1)=[O:31])([O-:38])=[O:37]
Reactant: O=C1NC(C(=O)O)C(c2ccco2)S1
Reactant: NCCO[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2ccco2)S1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.6 %

Procedure:
1.58 ml of triethylamine and 0.47 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 500 mg of 5-(furan-2-yl)2-oxothiazolidine-4-carboxylic acid and 476 mg of N-(2-nitrooxyethyl)amine nitrate in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 3.5 hours, after which the solvent was removed by distillation under reduced pressure. The crystals which precipitated were triturated with diisopropyl ether and collected by filtration. These crystals were recrystallized from methylene chloride, to give 400 mg of the title compound as colorless crystals, melting at 117°-118° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31](Cl)[O:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([NH:2][C:3]2[CH:23]=[CH:22][CH:21]=[C:5]([CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18](=[O:19])[NH2:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)[CH:4]=2)[O:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: CCOC(=O)c1coc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)n1

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-oxazole-4-carboxylic acid ethyl ester at 120° C.:
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.C(O)(=[O:24])C.OO>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1)=[O:24]
Reactant: CC(=O)O
Reactant: CSCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Agent: OO
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of 2.8 g. (0.009 mole) of 5-methylthiomethyl-2-nitro-3-phenylbenzofuran in 200 ml. of acetic acid is obtained by warming. The solution is cooled to 20° C., and 0.51 g. (0.0045 mole) of hydrogen peroxide in 15 ml. of acetic acid is added dropwise. After 20 hours, an additional 1.02 g. of 30 percent hydrogen peroxide in 20 ml. of acetic acid is added dropwise. After an additional 2.5 hours, the reaction is poured onto ice, the precipitate is collected by filtration and washed with water, then dissolved in a dichloromethane-diethyl ether mixture. This mixture is washed with water and saturated sodium chloride solution, then dried. Evaporation provides a solid which is dissolved in chloroform and eluted through a silica gel column with more chloroform. The desired product is eluted from the silica gel with ethyl acetate, recrystallized from a benzene-hexane mixture then from aqueous ethanol to provide yellow plates of 5-methylsulfinylmethyl-2-nitro-3-phenylbenzofuran, m.p. 162°-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])([O-:19])=[O:18]
Reactant: NC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccccc2[N+](=O)[O-])c1

Procedure:
To 3-hydroxybenzamide (0.137 g; 1 mmol) was added potassium carbonate (0.138 g; 1 mmol) and 2-nitrobenzyl bromide (0.216 g; 1 mmol) in anhydrous acetonitrile (10 ml). The mixture was heated under reflux for 5 hours.