Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](O)=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5]=1[CH2:24][CH2:25][CH3:26])(=[O:3])[CH3:2].O[N:28]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.C(OCC)(=O)C.CO>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:28])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5]=1[CH2:24][CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(C(C)=O)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1c(C(C)=O)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: 2 °C
Reaction time: 14 h
Yield: 90.8 %

Procedure:
To a solution of 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylic acid (74 mg) in dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (38 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg) and 3N methanol solution of ammonia (0.5 ml). After stirred at 2° C. for 14 hours, the resulting mixture was diluted with ethyl acetate. The organic phase was washed successively with 1N hydrochloric acid, water, aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxamide (67 mg) as colorless crystals.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[NH:23]O)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[NH:4].O[Li].O.S([O:34][CH3:35])(OC)(=O)=O.[CH3:36]N(C=O)C>>[CH3:36][O:1][NH:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22](=[NH:25])[NH:23][O:34][CH3:35])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[NH:4]
Reactant: COS(=O)(=O)OC
Reactant: N=C(NO)c1ccc(-c2ccc(-c3ccc(C(=N)NO)o3)cc2)cc1
Reactant: CN(C)C=O
Agent: [Li]O
Solvent: O
Product: CONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC)o3)cc2)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
To a suspension of the amidoxime 3 (1 mmol) in DMF (15 mL) was added LiOH.H2O (6 mmol, in 3 mL H2O) followed by dimethyl sulfate (5 mmol). The reaction was kept stirring overnight after which it was poured onto ice/water and the precipitate was filtered, washed with water and dried to give the desired compound in 92% yield; mp 214-215° C. 1H NMR (DMSO-d6); δ 3.75 (s, 6H), 6.12 (d, J=3.6 Hz, 1H), 6.17 (d, J=3.6 Hz, 1H), 7.76-8.00 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:22]Cl)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]=1[Br:7].[OH-].[Na+].O.O.[CH3:28][N:29]([CH3:33])[C:30](=[S:32])[S-:31].[Na+].CN(C)C=O>O>[CH3:28][N:29]([CH3:33])[C:30](=[S:31])[S:32][CH2:22][N:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]([Br:7])=[C:2]1[Br:1]
Reactant: O=S(=O)(c1c(Br)c(Br)n(CCl)c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)SCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.7 %

Procedure:
2,3-Dibromo-1-(chloromethyl)-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00194 mol) is added to a mixture of sodium hydroxide (0.084 g, 0.0021 mol), sodium dimethyldithiocarbamate dihydrate (0.376 g, 0.0021 mol) and dimethylformamide. The reaction mixture is stirred for six hours at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow gum. The gum is stirred with hexanes overnight and filtered to give the title product as a white solid (0.37 g, mp 185°-187° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH3:23][C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=2)=[O:13])=[CH:30][CH:31]=1)([CH3:24])[CH3:22]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A solution of 2,2'-dithiobisbenzoyl chloride (1.20 g, 3.50 mmol) in 25 mL of dichloromethane was added to a solution of 4-tert-butylaniline (1.04 g, 6.99 mmol) in 8 mL of pyridine at 23° C. The reaction mixture was stirred for 18 hours at 23° C. under nitrogen atmosphere. The mixture was concentrated, the residue triturated with 5% aqueous HCl, and the resulting solid was collected by filtration and washed with water to yield the crude product. The crude material was recrystallized from ethyl ether-ethanol to yield 0.24 g of the title compound, mp 135-138° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[ClH:25]>O1CCOCC1.C1COCC1.O1CCOCC1>[ClH:25].[ClH:25].[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of tert-butyl {1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbamate (1.27 g, 3.68 mmol) in HCl in Dioxane/THF (4M, 1:1; 10 ml) was stirred at rt. After 6.5 h more HCl in Dioxane (4M, 2 ml) was added and the resulting mixture stirred for a further 18 h. The mixture was filtered and the residue was washed with EtOAc to give the title compound (1.04 g, 89%) as a solid. 1H NMR (500 MHz CD3OD): 8.35 (s, 1H), 8.20 (dd, 1H), 7.60 (d, 1H), 4.46 (d, 2H), 3.66-3.56 (m, 1H), 3.48 (td, 2H), 2.28 (d, 2H), 1.90-1.80 (m, 2H); 13C NMR (125 MHz CD3OD): 153.5, 139.2, 136.3, 126.1, 123.9, 121.8, 120.0, 116.2, 115.9, 115.6, 115.3, 113.9, 45.2, 29.1; Mass Spectrum: M+H+ 246.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:13]([CH3:15])([CH3:14])[C:12]([O:11][CH2:9][CH3:10])=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)nc1
Reaction time: 48 h
Yield: 72.1 %

Procedure:
To a solution of 6-chloropyridin-3-ol (5 g, 38.6 mmol) and ethyl-2-bromo-2-methylpropanoate (6.01 ml, 40.5 mmol) in acetonitrile (50 mL) was added cesium carbonate (27 g, 83 mmol). The material was stirred vigorously for 48 hours. The mixture was taken up in water (100 ml) and ethyl acetate (100 ml) and transferred to a separatory funnel and shaken. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried (magnesium sulfate), filtered and stripped. The crude material was purified via preparative HPLC (silica gel; 50 g column) eluting with 5-30% ethyl acetate/hexanes to provide the desired product as light white-yellow mobile oil (6.78 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28](O)=[O:29])=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33].[CH2:35](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.C[O:58][C:59](=[O:65])[C@H:60]([CH:62]([CH3:64])[CH3:63])[NH2:61]>>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([N:61]([CH3:35])[CH:60]([CH:62]([CH3:64])[CH3:63])[C:59]([OH:58])=[O:65])=[O:29])=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: ClCCCl
Reactant: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)N(C)C(C(=O)O)C(C)C)cc2c1

Procedure:
A solution of 5-{1-[4-(3,3-Dimethyl-2-oxo-cyclohexyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (100 mg, 0.204 mmol) (from example 73A), EDC (58 mg, 0.306 mmol), HOBT (32 mg, 0.244 mmol), triethylamine (0.1 ml, 0.816 mmol), and L-valine methyl ester hydrochloride (41 mg, 0.244 mmol) were reacted followed by base hydrolysis as in Example 74 to yield (80 mg, 68%) MS (ES) m/e: 574.3 (M−1)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N+:9]([O-:12])[O:10][N:11]=[C:7]2[CH:6]=1.NO.O>CO>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8](=[N:9][OH:12])[C:7](=[N:11][OH:10])[CH:6]=1
Reactant: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: NO
Solvent: CO
Solvent: O
Product: ON=C1C=CC(Oc2ccc(C(F)(F)F)cc2Cl)=CC1=NO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole N-oxide (20.0 g, 61.0 mmol) and hydroxylamine (4.0 g, 120.00 mmol) in 50 ml of methanol is stirred at 45° for 18 hours. The reaction is cooled to RT and 10 ml of water is added. The resulting white solid which precipitates is collected and dried to give 4-(2-chloro-4-trifluoromethylphenoxy)-ortho-benzoquinone dioxime.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)=[O:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)Cl>[CH:17]12[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:19]3)[CH:10]1[NH:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:31])[O:32][CH3:33])[CH2:3]1)=[O:8])[CH2:18]2
Reactant: COC(=O)Cl
Reactant: N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 49.1 %

Procedure:
A vial equipped with a flea stir bar was charged with (R)-3-amino-N-(2-adamantyl)pyrrolidine-1-carboxamide (25 mg, 0.095 mmol), i-Pr2NEt (0.07 mL, 0.38 mmol) and CH2Cl2. The solution was stirred and methyl chloroformate (0.009 mL, 0.11 mmol) was added. The mixture was stirred overnight at rt and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (R)-methyl 1-(2-adamantylcarbamoyl)pyrrolidin-3-ylcarbamate (15 mg, 49%). LC-MS Method 1, tR=1.5 min, m/z=322; 1H NMR (CDCl3) 1.60-2.00 (15H), 2.20 (m, 1H), 3.26 (m, 1H), 3.46 (m, 2H), 3.63 (m, 1H), 3.69 (s, 3H), 3.96 (s, 1H), 4.30 (1H), 4.60 (1H), 4.89 (d, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])=[NH:11])[CH2:2]2.[Br:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27]>CN(C=O)C>[Br-:24].[C:26]([CH2:25][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH2:11])=[N:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])[CH2:2]2)([OH:28])=[O:27]
Reactant: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CN2CCC1CC2
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CN(C)C=O
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NC1C[N+]2(CC(=O)O)CCC1CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)-N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine (Intermediate 4, 152 mg, content ca. 66%, 0.30 mmol) and benzyl bromoacetate (Aldrich, 0.052 mL, 0.33 mmol) are treated with DMF (1 mL) and the mixture stirred at r.t. for ca. 18 h. The crude mixture is purified by preparative HPLC (5 mM ammonium formate in H2O: CH3CN gradient) and further on a PoraPak Rxn RP cartridge (Waters, 6 mL), eluting with 0% to 100% acetonitrile in water. Drying under vacuum yields the title compound (23 mg).
Reaction SMILES: CI.[NH2:3][C:4]1[CH:9]=[C:8](N)[NH:7][C:6](=[S:11])[N:5]=1>[OH-].[Na+]>[NH2:5][C:6]([NH2:7])=[S:11].[C:8](#[N:7])[CH2:9][C:4]#[N:3]
Reactant: Nc1cc(N)[nH]c(=S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: N#CCC#N
Product: NC(N)=S

Procedure:
Methyl iodide (169.0 g., 1.19 mole) is added in one portion to a stirred solution of 4,6-diaminopyrimidine-2(1H)thione (146 g., 1.02 mole) in 1.0 liter 1N sodium hydroxide. The thione starting material is obtained by reaction of thiourea and malononitrile according to Kikugawa, et al., Chem. Pharm. Bull., 25(7), 1811-1821 (1977). In about five minutes following the addition a precipitate forms. After stirring overnight, the reaction mixture is filtered and air-dried affording 135.1 g. (81%) of 4,6-diamino-2-(methylthio)pyrmidine; m.p. 185°-186° (recrystallized from acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]([O:17]COCCOC)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:17])=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)=[O:4]
Reactant: COCCOCOc1c(-c2ccccc2)cc(C(=O)OC)cc1-c1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
At ambient temperature, to a stirred solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.608 g, 4.098 mmol) in CH2Cl2 (16.08 mL) was added portionwise trifluoroacetic acid (16.08 mL). After 1 h, the reaction was diluted with ether (100 mL), washed sequentially with H2O (3×), with sat. aq. NaHCO3 (3×), with brine (3×), dried (MgSO4) and concentrated to give 1.240 g (99%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ3.83 (s, 3H), 7.39-7.50 (m, 6H), 7.55-7.57 (m, 4H), 7.78 (s, 2H), 9.28 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2([CH3:17])OCCO2)[CH:9]=[CH:8][C:7]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][N:4]=[C:12]([C:10]1[CH:9]=[CH:8][C:7]([OH:18])=[C:6]([NH2:5])[CH:11]=1)[CH3:17]
Reactant: CC1(c2ccc(O)c(N)c2)OCCO1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(C)c1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of O-methylhydroxylamine hydrochloride (535 mg, 6.40 mmol), 2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D62 (250 mg, 1.28 mmol) and potassium carbonate (442 mg, 3.20 mmol) in ethanol (10 mL) was heated to reflux for 2 hr. The mixture was cooled to rt and concentrated to dryness under vacuum and the residue partitioned between DCM and water. The organic phase was separated washed with brine, dried (MgSO4) and concentrated to dryness in vacuo. The residue was purified using silica gel chromatography eluting with 0 to 10% MeOH in DCM. The title product was isolated as a pale brown solid, 224 mg, 97%.
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][N:5]2[C:6](=[O:14])[NH:7][C:8](=[O:13])[C:9]([CH:10]3[CH2:12][CH2:11]3)=[C:4]2[C:3]=1[O:18][CH3:19].[N+:20](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>>[NH2:20][N:7]1[C:8](=[O:13])[C:9]([CH:10]2[CH2:11][CH2:12]2)=[C:4]2[C:3]([O:18][CH3:19])=[C:2]([Cl:1])[C:16]([F:17])=[CH:15][N:5]2[C:6]1=[O:14]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: COc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Product: COc1c(Cl)c(F)cn2c(=O)n(N)c(=O)c(C3CC3)c12
Yield: 71.5 %

Procedure:
The title compound (0.09 g) was prepared from 6-chloro-4-cyclopropyl-7-fluoro-5-methoxypyrido[1,2-c]pyrimidine-1,3-dione (0.12 g, 0.42 mmol [Example 11]) and 2,4-dinitrophenylhydroxylamine (0.11 g, 0.5 mmol) using the procedure used to prepare Example 3. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, 1H), 5.52 (bs, 2H), 3.84 (s, 3H), 1.90-1.82 (m, 1H), 1.07-1.00 (m, 2H), 0.62-0.55 (m, 2H). MSCI: m/z 300 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[CH:21]([C:23]1[N:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1)=[CH2:22].C(O)(=O)C>C(O)CC.O>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:21][CH2:22][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)=[N:28][CH:27]=1)(=[O:31])[CH3:30]
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reactant: C=Cc1ccc(C(C)=O)cn1
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CCN2CCN(c3cccc4cc(C(=O)N(C)C)oc34)CC2)nc1
Temperature: 69 °C

Procedure:
A reaction mixture of N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.078 g, 0.29 mmol) (Example 39d), 1-(6-vinylpyridin-3-yl)ethanone (0.15 g, 1.00 mmol) and acetic acid (0.016 mL, 0.29 mmol) in n-propanol (1.5 mL) and water (0.10 mL) was heated at 69° C. for 2 days. The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.CON(C)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=[O:15]>C1(C)C=CC=CC=1.O1CCCC1.BrCCBr>[CH3:22][C:18]1[N:17]=[C:16]([C:14](=[O:15])[CH2:7][C:6]2[CH:9]=[CH:10][C:3]([CH3:2])=[CH:4][CH:5]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1cccc(C)n1
Reactant: Cc1ccc(CCl)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC(=O)c2cccc(C)n2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a slurry of magnesium turnings (406 mg, 16.7 mmol) in toluene (10 mL) is added 4-methylbenzylchloride (10 mg, 0.06 mmol) dropwise in tetrahydrofuran (0.2 mL). Two drops of 1,2-dibromoethane are added, the mixture heated to 50° C., and allowed to cool to room temperature. This process is repeated until reaction initiates. 4-Methylbenzylchloride (1.5 g, 10 mmol) in tetrahydrofuran (7 mL) is added slowly while keeping the internal temperature below 32° C. After the addition is complete the reaction is stirred at room temperature for 1 h. The reaction mixture is added dropwise over 5 minutes to a solution of 6-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide (Prep 250, 1 g, 5.6 mmol) in toluene (5 mL). The reaction is stirred for an additional 45 minutes. The reaction is quenched with 1 N hydrochloric acid and stirred for 30 minutes. The aqueous layer is neutralized with saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude residue is chromatographed on SiO2 (50% ethyl acetate/hexane to 75% ethyl acetate/hexane) to yield the title compound, 633 mg (25%), as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: C1CCNC1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCCC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with pyrrolidine in ethanol to provide yellow crystals of 2-nitro-3-phenyl-5-(1-pyrrolidylmethyl)benzofuran, m.p. 111°-112.5° C., having the structure
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][N:12]=[N:11]2)[CH:5]=1.N(C1C=C(C=CC=1)C(OC)=O)=[N+]=[N-].O=S(Cl)Cl.CNC.[C:40]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[CH3:41].[Li]>C1COCC1>[C:44]([O:43][C:40](=[O:42])[CH2:41][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][N:16]([CH3:17])[CH3:18])=[CH:13][N:12]=[N:11]2)[CH:5]=1)=[O:19])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)c1cccc(-n2nncc2CN(C)C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CNC
Agent: COC(=O)c1cccc(N=[N+]=[N-])c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from 3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-benzoic acid methyl ester [prepared from methyl 3-azidobenzoate following the synthetic steps i.) to iii.) as described in the preparation of Example K5 and reacting the obtained product with SOCl2 in THF at 0 to 23° C. for 1 h, followed by addition of dimethylamine (7.9 M in H2O) and stirring at 23 to 70° C. for 1 h.] (2.14 g, 8.22 mmol) by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (2.90 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[C:15]1[N:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[O:7]([C:15]1[N:16]=[N:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(Oc2ccccc2)nn1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(Oc2ccc(Oc3ccccc3)nn2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
Phenol (Aldrich, 1.88 g, 20 mmol) in tetrahydrofuran (50 mL) was treated with potassium tert-butoxide (Aldrich, 2.24 g, 20 mmol) at ambient temperature for 10 minutes. The product of Example 27A (3.0 g, 14.5 mmol) was then added and the reaction mixture was stirred at 60° C. for 10 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×10 mL). The organic phase was concentrated affording the title compound as a solid (3.2 g, yield, 84%). 1H NMR (MeOH-d4, 300 MHz) δ 7.14–7.28 (m, 6H), 7.38–7.48 (m, 6H) ppm. MS (DCl/NH3) m/z 265(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14][CH3:15])[CH3:12]>C(OCC)C>[C:7]([C:6](=[C:14]1[CH2:15][CH2:12][CH2:11][NH:13]1)[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:8]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: N#CC(=C1CCCN1)c1ccc(Cl)cc1

Procedure:
Stir 106 g of 2-methoxypyrroline-1, 243.5 g of 4-chlorobenzylcyanide and 9 ml of triethylamine for 20 hours at 110°. After cooling, add 200 ml of diethyl ether thereto and filter off the formed precipitate (80.9 of the title compound). Distil off the solvent and the 4-chlorobenzylcyanide under a vacuum to obtain a further 42 g of the title compound (m.p. 135° to 137°) for a total yield of 122.9 g (52% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(O)CCC.O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)=[N:16][CH:17]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1ccc(CCO)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OCCc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-aminophenyl)ethanol (0.72 mol), 5-bromo-2-chloropyrimidine 4 (0.72 mol), sodium iodide (0.72 mol), and diisopropylethylamine (1.45 mol) in n-butanol (400 mL) is heated at reflux for 16 h. The reaction is cooled to rt and the mixture is diluted with water. The light yellow solid that precipitates is filtered to give 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol 18. 1H NMR (300 MHz, d6-DMSO) δ 9.72 (s, 1H), 8.52 (s, 2H), 7.55 (m, 2H), 7.09 (d, 2H), 4.64 (m, 1H), 3.52 (m, 2H), 2.65 (m, 2H). MS (m/z) (M+1)+: 294.1, 296.1.