Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([F:15])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[Br:14])=[O:4].[H-].[Na+].[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:15])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:9]=[C:8]2[Br:14])=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2[nH]nc(Br)c2c1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c(Br)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reaction time: 0.42 h
Yield: 30.7 %

Procedure:
Under ice-cooling, to a solution of 2.99 g of 3-bromo-4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-d in 30 ml tetrahydrofuran was added 526 mg of 60% sodium hydride, and the mixture was stirred for 25 minutes. Then, 3.21 g of triphenylmethyl chloride was added and the mixture was stirred at the same temperature for 15 minutes and further stirred at room temperature for 45 minutes. The reaction mixture was ice-cooled again, saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:9), and the resulting crystals were recrystallized from diisopropyl ether, to give 1.73 g of the title compound as white needles.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.Cl[Cu]>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: Cl[Cu]
Solvent: CCO
Solvent: O
Product: Nc1ccn(-c2ccccc2)n1
Reaction time: 3 h
Yield: 79 %

Procedure:
Example 1 was repeated using the following amounts of reagents: 5 g (0.031 mole) of 1-phenyl-3-amino-2-pyrazoline were suspended in 25 ml of ethanol and 2 ml of H2O, under addition of 0.1 g (0.001 mole) of CuCl and 0.064 g (0.001 mole) of Cu, under an oxygen head. Oxidation lasted about 3 hours. 3.9 g of 1-phenyl-3-aminopyrazole were obtained.
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[CH2:45]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60](=O)[CH2:61][CH:62]2[C:71]3[C:66](=[CH:67][C:68]([Br:72])=[CH:69][CH:70]=3)[CH2:65][CH2:64][O:63]2)[CH2:56][CH2:55]1)[CH3:46]>>[CH2:45]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[N:54]1[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH:62]2[C:71]3[C:66](=[CH:67][C:68]([Br:72])=[CH:69][CH:70]=3)[CH2:65][CH2:64][O:63]2)[CH2:56][CH2:55]1)[CH3:46]
Reactant: CCOc1ccccc1N1CCN(C(=O)CC2OCCc3cc(Br)ccc32)CC1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: CCOc1ccccc1N1CCN(CCC2OCCc3cc(Br)ccc32)CC1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 2-ethoxyphenylpiperazine (XI) and the resulting amide, 1-(2-ethoxyphenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 3.7 mmol) is reduced following the general procedure of EXAMPLE 50 making non-critical variations, to give the title compound, IR (neat) 2816, 1501, 1480, 1448, 1240, 1143, 1124, 1046, 1110 and 748 cm-1 ; NMR (300 MHz, CDCl3) 7.31-7.26, 7.00-6.90, 6.85-6.83, 4.78, 4.14-4.03, 3.78-3.70, 3.13, 3.00-2.90, 2.13, 1.99, 1.45; CMR (75 MHz, CDCl3) 151.37, 141.19, 137.0, 136.1, 131.5, 129.1, 126.4, 122.5, 120.8, 119.8, 117.9, 112.2, 74.2, 63.4, 62.6, 54.6, 53.5, 50.4, 33.0, 28.7 and 14.8 δ; HRMS Calcd for C23H29N2O2Br1 =444.1413, found=444.1400.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccccc4C3)c(F)c21
Yield: 36.6 %

Procedure:
136 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 179 mg of isoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 68 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[N+](C1C=CC=CC=1)([O-])=O>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:14]1[C:13]1[CH:16]=[CH:17][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1ccccc1O
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Yield: 73 %

Procedure:
A mixture containing 5.45 g. (0.05 mole) of o-aminophenol and 6.10 g. (0.05 mole) of p-hydroxybenzaldehyde in 75 ml. of nitrobenzene was heated to reflux for 5 hr. On cooling to 30° a dark solid appears which was filtered, washed with hot toluene, and air-dried. Recrystallization from ethanol gave a 73% yield of 4-(2-benzoxazolyl)phenol (mp 255°-258°).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].Cl.[N:14]([O-])=O.[Na+]>O>[CH3:9][N:6]1[C:7]2[CH:8]=[N:14][NH:1][C:2]=2[C:3](=[O:12])[N:4]([CH3:11])[C:5]1=[O:10]
Reactant: O=N[O-]
Reactant: Cc1c(N)c(=O)n(C)c(=O)n1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2[nH]ncc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Step 1 intermediate (4.0 g, 23.634 mmol) in a mixture of ice (24 g) and concentrated HCl (5 ml) was added a solution of sodium nitrite (1.42 g, 20.580 mmol) in water (5 ml). The resulting suspension was stirred below 10° C. for 30 min. The solid formed at this stage was removed by filtration and the filtrate was added slowly with continuous stirring to 20% aq. NaOH (20 ml) by maintaining the temperature below 10° C. After addition the basic solution was filtered and neutralized with hydrochloric acid (5 N HCl). The precipitate separated was filtered and dried to get 300 mg of the product as dark orange solid; 1H NMR (300 MHz, DMSO-d6): δ 3.45 (s, 3H), 3.52 (s, 3H), 7.53 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][N:36]=[CH:35]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:20]1([C:18]([N:16]2[CH2:17][CH:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:40]5[CH:39]=[C:38]6[C:34]([CH:35]=[N:36][NH:37]6)=[CH:33][CH:32]=5)=[CH:3][CH:4]=4)[C:9](=[O:23])[NH:10][N:11]=3)[CH2:15]2)=[O:19])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cn[nH]c4c3)cc2)C1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 0.186 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 9.80 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (50 mg, 0.205 mmol)) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.7 mL, 1.400 mmol) was stirred at 100° C. in an oil bath for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was adjusted to pH˜6-6.5 using 1N aq HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-90% acetonitrile/water+0.1% NH4OH) provided the title compound as a white solid (20 mg, 26%). MS(ES)+ m/e 415.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OC)(C)(C)C>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:13][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]
Reactant: Cc1ccccc1I
Reactant: CN(C)CCC(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Product: Cc1ccccc1OC(CCN(C)C)c1ccccc1
Temperature: 130 °C
Yield: 89.1 %

Procedure:
A mixture of N,N-dimethyl-3-hydroxy-3-phenylpropylamine (0.9 g, 5 mmol), 2-iodotoluene (1.31 g, 6 mmol), cuprous iodide (0.2 g) and cesium carbonate (1.8 g, 5.5 mmol) was stirred under nitrogen at 130° C. until the reaction was complete as determined by 1H NMR. The reaction mixture was cooled to room temperature, diluted with methyl t-butyl ether (10 mL), filtered, and rinsed with more methyl t-butyl ether. The filtrate was extracted with diluted hydrochloric acid solution and the aqueous layer was washed with more methyl t-butyl ether. The aqueous was adjusted to pH>10 by the addition of sodium hydroxide solution, then extracted with methyl t-butyl ether twice. The combined extracts were washed with water and then evaporated to dryness to give 1.2 g of N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine as a light yellow oil. 1H NMR (CDCl3) δ 7.45-7.2 (m, 5H), 7.12 (d, J=6.8 Hz, 1H), 7.0 (dd, J=8.0, 7.6 Hz, 1H), 6.78 (dd, J=8.4, 6.8 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.24 (dd, J=8.1, 4.8 Hz, 1H), 2.46 (t, J=7.3 Hz, 2H), 2.33 (s, 3H), 2.24 (s, 6H), 2.3-2.1 (m, 1H), 2.05-1.9 (m, 1H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(CC)[CH3:2].C(#N)C.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(OO)(CC)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:14])[CH3:2]
Reactant: CCC(C)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCC(C)OO
Agent: O=O
Solvent: CC#N
Product: CC(=O)c1ccccc1
Yield: 11 %

Procedure:
A solution of 10 mL of sec-butylbenzene (64.3 mmoles), 3.75 mL of acetonitrile and 0.64 mmoles of N-hydroxyphthalimide is stirred at 70° C. for 24 hours in an atmosphere of oxygen at a pressure of 1 bar. 1H-NMR analysis of the reaction mixture showed a secbutylbenzene conversion of 20% with a selectivity in sec-butyl hydroperoxide of 89% (result confirmed by iodometric titration) and 11% of acetophenone. The acetonitrile is removed by distillation and 0.57 mmoles of N-hydroxyphthalimide are recovered.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6]N[CH2:8]2.[C:17]([BH3-])#[N:18].[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:18]([CH2:17][CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:3]=1)[CH2:8]2
Reactant: [BH3-]C#N
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCc1ccccc1)CC2
Reaction time: 1 h
Yield: 190.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and phenylacetylaldehyde (0.82 ml, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for one hour. The reaction mixture was then cooled under an ice bath and precipitate filtered off. The solids were washed with hexane and oven dried to give the title compound (1.16 g, 95% yield) as an orange solid, mp=120-122° C.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)N(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C(C)C)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 49.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-isopropyl-N-methylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 69.2 %

Procedure:
To a solution of indole-5-carboxaldehyde (2.00 g, 13.8 mmol) in dimethylformamide (50 mL) were added sodium hydride (60% oil dispersion; 828 mg, 20.7 mmol) and p-toluenesulfonyl chloride (3.16 g, 16.6 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 13 h at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5:1 hexane/ethyl acetate) to afford 1-(4-methylphenyl)sulfonylindole-5-carboxaldehyde (2.86 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (2.0 g, 11 mmols), ethyl 4-bromobutanoate (8.7 g, 45 mmols), potassium carbonate (2.3 g, 17 mmols) and N,N-dimethylformamide (50 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[4-(ethoxycarbonylmethyl)phenyl]aminobutanoate (2.4 g, 74%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[NH:11]
Reactant: NO
Reactant: N#Cc1ccc2occc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2occc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 172.6 %

Procedure:
Prepared using General Procedure 1. To a flask containing benzofuran-5-carbonitrile (200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (176.7 mg, 2.54 mmol) and Na2CO3 (154 mg, 1.42 mmol). The mixture was stirred at 75° C. overnight then concentrated, re-dissolved in DCM and washed with NaHCO3. The combined organic layers were dried over Na2SO4, and concentrated to provide 222 mg of crude N-hydroxybenzofuran-5-carboximidamide INT-68 as a white solid which was used directly in the next step without purification. LCMS-ESI (m/z) calculated for C9H8N2O2: 176.2; found 177.1 [M+H]+, tR=0.83 min.
Reaction SMILES: Br[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N-:15]=[N+:16]=[N-:17].[Na+]>CC(C)=O.O>[N:15]([CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N+:16]=[N-:17]
Reactant: BrC1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 87.5 %

Procedure:
9-Bromo-9H-fluorene (1.00 g, 4.08 mmol) was dissolved in acetone (7 mL). To this was added a solution of NaN3 (1.33 g, 20.4 mmol) in H2O (3 mL). The resulting solution was stirred overnight. Acetone was removed by concentration under reduced pressure. The resulting aqueous mixture was extracted with CH2Cl2 (2×15 mL), and the organic layers were combined, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The resulting solid residue was purified by silica gel flash chromatography, eluting with hexanes, to give azide 2j as a white solid (0.74 g, 3.57 mmol, 87% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:21]I.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:21])[C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(C(=O)O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH 60% dispersed in mineral oil (0.024 g; 0.611 mmol) was added to a solution of methyl 4-(3-fluorophenylamino)benzoate in THF (3 mL). After stirring the resulting solution for 10 minutes methyl iodide (0.062 mL; 0.994 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with water, acidified with a 6N solution of hydrochloride acid and extracted with ethyl acetate. The organic layer was dried to yield 0.119 g (quantitative) of the title compound as a brown solid. The compound was used without further purification.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][O:12]P(O)(O)=O)[C@@H:8]([OH:17])[C@H:7]2[OH:18])[C:4]([NH2:19])=[C:3]([C:20]([NH2:22])=[O:21])[N:2]=1.[N:23]([O-])=O.[Na+].N>C(O)C>[C@@H:6]1([N:5]2[C:4]3[N:19]=[N:23][NH:22][C:20](=[O:21])[C:3]=3[N:2]=[CH:1]2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:17])[C@H:7]1[OH:18]
Reactant: O=N[O-]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c1N
Agent: N
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]nnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
The AICAR [for preparation see Synthesis, 2003, No 17, 2639] (1 g, 3.87 mmol) was added to a solution of chlorhydrique acid 6N (25 mL) at −30° C. A solution of sodium nitrite 3M (4 ml, 11.62 mmol) was added and the mixture was stirred at −30° for 2 hours. A pre-cooled (−30° C.) solution of ethanol (25 mL) was added. A solution of ammonia (28%) was added at −20° C. to pH=7. The reaction mixture was evaporated to dryness. The crude product was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (0.81 gr) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C1N2CCN(CC2)C1>O1CCOCC1.O>[N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[C:16](=[CH2:17])[C:15]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)OC)C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2,4-Dinitrobenzaldehyde was dissolved in dioxane and water, methyl acrylate and triethylenediamine were added thereto at room temperature, and the whole was stirred to obtain methyl 2-[(2,4-dinitrophenyl) (hydroxy)methyl]acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[C:19]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cccc(CCN)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(C)=O)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methoxyphenethylamine (56.6 g, 0.37 m) and triethylamine (38.0 g, 0.38 m) in CHCl3 (900 ml) was added acetyl chloride (33.0 g, 0.42 m) dropwise over a period of 30 minutes at 20°-25° C., and then the reaction was stirred overnight. The mixture was extracted with 500 ml ice water, then extracted further with 2×500 ml cold water. The chloroform layer was dried over MgSO4 and concentrated to N-acetyl-3-methoxyphenethylamine as an oil (90 g).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: COc1ccc(B(O)O)c(Cl)c1
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: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 41.9 %

Procedure:
To a mixture of 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (2.51 g, 10 mmol) in dioxane (3.3 mL) and water (3.3 mL), were added 2-chloro-4-methoxyphenylboronic acid (2.3 g, 12.5 mmol) and Na2CO3 (6.3 g). The mixture was purged with nitrogen gas for 10 min, then Pd(PPh3)4 (1.2 g, 1.0 mmol) was added. The mixture was stirred in a sealed vessel at 85° C. for 6 hrs, then extracted by ethyl acetate. The organic layer was washed with water, dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (10/1) yielded 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (1.31 g). tR=2.96 min (method 1).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][CH:8]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:6]1[N:5]=[N:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Na]
Product: Clc1ccc(OCc2ccccc2)nn1
Reaction time: 24 h
Yield: 90 %

Procedure:
Sodium metal (3.1 g) was added to benzyl alcohol (75 mL) and gently warmed to 50° C. for 30 minutes until all the sodium metal dissolved. A solution of 3,6-dichloropyridazine (135 mmol) in benzyl alcohol (75 mL) was added. The reaction mixture was kept at 100° C. for 24 hours. Excess benzyl alcohol was evaporated and the residue was extracted with ethyl acetate (3×100 mL) and the ethyl acetate extract was washed with water. The resulting ethyl acetate layer was collected, dried, filtered, and the filtrate was evaporated to afford the title compound (90%, 26.7 g); mp, 77-78° C.