Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[IH:12].[PH2](O)=O.[OH-].[Na+]>O>[I:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:3]([OH:2])=[O:11])[CH:9]=1
Reactant: I
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: O=[PH2]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(I)ccn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57% hydriodic acid (13.3 mL) and 50% aqueous hypophosphorous acid (0.66 mL) was stirred at 85° C. for 2 h and then was stirred at 107° C. overnight. The mixture was cooled to 95° C. At this temperature were added in 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL), followed by the addition of water (15.2 mL). The mixture was cooled to rt and stirred at rt for 1 h. The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give a yellow solid 11a, 4-Iodopicolinic acid (3.5 g, 66%): 1H NMR (300 MHz, DMSO d6) δ 8.39 (d, J=5.1, 1), 8.35 (d, J=1.8, 1), 8.07 (dd, J=1.7, 5.2, 1); MS (ESPOS): 250.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[O:7][C:6](=[O:8])[CH:5]([F:9])[CH2:4]1)[CH3:2].C1(C)C=CC=CC=1.CC(C[Al]CC(C)C)C.Cl>O1CCCC1>[CH2:1]([CH:3]1[O:7][CH:6]([OH:8])[CH:5]([F:9])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(F)C(=O)O1
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1CC(F)C(O)O1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 19.8 g (0.15 mol) of 5-ethyl-3-fluorodihydro-2(3H)-furanone dissolved in 500 ml of dry tetrahydrofuran was added at -70° C., 128 ml of a 1.4 M toluene solution of Dibal-H. The solution was stirred at -70° C. for one hour and then added cautiously to ice water. The resulting mixture was adjusted to pH~1 with 200 ml of 1 N hydrochloric acid and then extracted with methylene chloride. The solution was dried (MgSO4) and the solvent removed under reduced pressure to give 20 g of crude product. Distillation afforded 13.13 g of 5-ethyl-3-fluorotetrahydro-2-furanol: bp 45°-46° C. (0.1 mm Hg).
Reaction SMILES: C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=CC(F)=CC=1C1N=C(NC2C=C3C(=CC=2)CNCC3)C(=O)N(C)C=1)(=O)C.[Br:46][C:47]1[N:52]=[C:51]([NH:53][C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][N:58](C(OC(C)(C)C)=O)[CH2:57]3)[C:50](=[O:70])[N:49]([CH3:71])[CH:48]=1>>[Br:46][C:47]1[N:52]=[C:51]([NH:53][C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][NH:58][CH2:57]3)[C:50](=[O:70])[N:49]([CH3:71])[CH:48]=1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)c1=O
Agent: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCNC4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CNC3)c1=O

Procedure:
Following the procedures as described for 129b and starting with 460 mg of tert-butyl 5-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)isoindoline-2-carboxylate, 231e was obtained as a yellow solid (352 mg, 99%). MS: [M+H]+ 321
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:9]2)[CH2:3][C:4]#[N:5].O.NN.NC1C=C[NH:31][N:30]=1>CCO>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:2]3[CH:3]=[C:4]([NH2:5])[NH:30][N:31]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)CC#N)ccc21
Reactant: Nc1cc[nH]n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc3[nH]ccc3c2)n[nH]1
Yield: 41 %

Procedure:
To a solution of 3-Oxo-3-(1-triisopropylsilanyl-1H-indol-5-yl)-propionitrile (490 mg, 1.44 mmol) in 15 mL of absolute EtOH, 720 μL of hydrazine monohydrate (14.4 mmol) were added and the reaction refluxed for 18 hours. LC-MS showed complete conversion to the aminopyrazole and also silyl deprotection. The mixture was concentrated under reduced pressure, and purified with SiO2 column (eluent gradient from 100% DCM to DCM:MeOH 9:1) to afford the title compounds (120mg, yield: 41%)
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)C.BrBr.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[C:19]([O:18][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCCCCC(CCC1=C(OC(C)=O)CCC1)OC(C)=O
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCC1=CCCC1=O)OC(C)=O
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-acetoxy-2-(3-acetoxyoctyl)cyclopent-1-ene (59.2 g.)[prepared as described in (e) above] in dry carbon tetrachloride (350 ml.) was added dropwise, during 30 minutes, a solution of bromine (32 g.) in dry carbon tetrachloride (100 ml.) at -10° to -5°C. The solution was stirred for a further 20 minutes without cooling. Triethylamine (22.2 g.) was then added and the resulting mixture stirred and refluxed for 90 minutes. The mixture was filtered, and the filtrate washed with aqueous 2N sodium carbonate and with water. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the residue was distilled, in the presence of a few crystals of potassium acetate, at 132°-168°C./0.25 mm.Hg, to give crude 2-(3-acetoxyoctyl)cyclopent-2-enone. This was redistilled, with potassium acetate, at 116°-135°C./0.15 mm.Hg to give 2-(3-acetoxyoctyl)cyclopent-2-enone (28.7 g.), nD28 = 1.470.
Reaction SMILES: C1C=C2C([N:9]([CH2:12][C:13](O)=[O:14])C(=O)C2=CC=1)=O.S(Cl)(Cl)=O.[CH2:20]([NH:24][C:25]1[C:30]([C:31](=O)[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN>C1(C)C=CC=CC=1.N1C=CC=CC=1.O.CN(C)C=O>[CH2:20]([N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][N:26]=2)[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[C:12]([NH2:9])[C:13]1=[O:14])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: CCCCNc1ncccc1C(=O)c1cccc(OC)c1
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCn1c(=O)c(N)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a suspension of N-phthaloylglycine (4.76 g, 23.2 mmol) in toluene (24 ml) were added thionyl chloride (5.08 ml, 69.6 mmol) and dimethylformamide (0.4 ml), and the mixture was stirred at 50-60° C. for 30 minutes, cooled, and concentrated under reduced pressure to remove the solvent. To the resulting solid was added toluene (12 ml), and further thereto were added a solution of 2-(butylamino)-3-(3-methoxybenzoyl)pyridine (3.30 g, 11.6 mmol) in toluene (15 ml) and pyridine (27 ml), and the mixture was stirred at 80-90° C. for 2 hours. After allowed to cool, to the mixture were added potassium carbonate (9.62 g, 69.6 mmol) and N,N-dimethylformamide (54 ml), and the mixture was further stirred at 90-100° C. for 8 hours. After allowed to cool, a 40% aqueous methylamine solution (4.99 ml, 58.0 mmol) was added, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, and the mixture was extracted with toluene. The extract was washed successively with 1 N hydrochloric acid, water, a 5% aqueous sodium hydrogen carbonate solution and a 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was recrytallized from 2-propanol to give the title compound (2.30 g, 7.11 mmol, 61%) as colorless prisms.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH:12]1[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15](=[O:25])[N:14]([CH3:26])[CH2:13]1>>[CH3:26][N:14]1[CH2:13][CH:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15]1=[O:25]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: CNc1ccccc1
Product: CN1CC(CCN(C)c2ccccc2)c2nc3ccccc3n2C1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 15 mL of N-methylaniline was added 3.5 g (0.0133 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one. The reaction mixture was heated to 90° C. (oil bath) for 2 days, and the excess N-methylaniline removed in vacuo at 80° C., 0.5 mm Hg. The residue was dissolved in 100 mL of CH2Cl2, washed with 2×100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to high vacuum (0.5 mm, Hg) at 85° C. for 2 hr, and then crystallized from iso-octane/toluene to give 2.3 g (52%) of analytically pure crystals, mp 130°-31° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[OH:21])[CH3:2].C(C1N=C(C2C=C(O[CH:43]3[CH2:60][CH:59]4[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:44]3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:9]=[C:8]2[O:21][CH:43]1[CH2:60][CH:59]2[CH:45]([C:46](=[O:66])[N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]3[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]2=[O:61])[CH2:55]3)[CH2:44]1)[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: CCc1c(OC)ccc2c(O)cc(-c3nc(C(C)C)cs3)nc12
Product: CCc1c(OC)ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc12

Procedure:
The title compound was prepared from 8-ethyl-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (69) and intermediate 43 following the procedure (Steps D-F) reported for the preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (46): m/z=661 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=1)=O.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].C([SiH](CC)CC)C>O>[F:17][C:18]([F:23])([F:22])[C:19]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=1)=[O:20]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(CCCBr)c1ccc2[nH]c(=O)oc2c1
Agent: CC[SiH](CC)CC
Solvent: O
Product: O=C(OCCCCc1ccc2[nH]c(=O)oc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 100 ml three-necked round-bottomed flask equipped with dropping funnel, thermometer, and N2 inlet were added 10 g (0.035 mol) 6-(4-bromobutyryl)benzoxazolone and 26.08 ml (0.35 mol) trifluoroacetic acid. To the stirring suspension was added dropwise 12.93 ml (0.080 mol) triethylsilane, and the reaction stirred at room temperature fo 16 hours. The reaction was then poured into water, and the resulting white solid filtered and washed with water. It was then suspended in isopropyl ether, stirred, and filtered to afford white solid 6-(4-trifluoroacetoxybutyl)-benzoxazolone, m.p. 100°-103° C., 10.47 g (98.7%).
Reaction SMILES: C[B-](F)(F)F.[K+].[CH2:7](Cl)Cl.FC(F)(F)S(O[C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1)(=O)=O.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:7][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1cc2c(c(OS(=O)(=O)C(F)(F)F)c1)CCCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C)c2c(c1)CCCC2
Temperature: 25 °C

Procedure:
The ester is formed according to the method of Molander et al. (J. Org. Chem. 68, 5534, (2003)). To a stirring suspension of potassium methyltrifluoroborate (629.0 mg, 5.2 mmol) Cs2CO3 (5.0 g, 15.5 mmol), PdCl2(dppf).CH2Cl2 (46.0 mg, 0.057 mmol), and triflate (46.3) (2.0 g, 5.7 mmol) in 50 mL THF is added water (5 mL) under an argon atmosphere. Stirring the mixture at reflux until TLC confirms the consumption of the starting material. The mixture is cooled to room temperature, and is diluted with water and extracted with ether. The combined organic layers are dried (MgSO4) and concentrated under reduced pressure. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford ester 46.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[NH:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C([O-])(=O)C.N1C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
1H-pyrazole-4-carboxylic acid ethyl ester (1.00 g, 7.14 mmol) and 1H-indol-5-ylboronic acid (1.15 g, 7.14 mmol) were dissolved in N,N-dimethylformamide (70 mL). Cupper (II) acetate (0.972 g, 5.35 mmol) and pyridine (1.2 mL, 14.8 mmol) were added, and the mixture was stirred for 3 days at room temperature. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give the title compound (1.40 g, 5.47 mmol, 77% Yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](#[N:9])[CH:7]=[CH2:8]>>[C:6]([CH2:7][CH2:8][NH:1][CH2:2][CH2:3][CH2:4][OH:5])#[N:9]
Reactant: NCCCO
Reactant: C=CC#N
Product: N#CCCNCCCO

Procedure:
In a third alternative synthesis of monomer I, 3-aminopropanol is added to acrylonitrile yielding 3-(2-cyanoethyl)aminopropanol, which in turn is converted in two steps to 3-[N-(2-cyanoethyl)-N-formylamino]propanol. The nitrile function of the latter is catalytically reduced to a primary amine function which in turn is exhaustively alkylated with a methyl halide to yield a 3-[N'-formyl-N'-(3-hydroxypropyl)amino]-N,N,N-trimethyl-1-propanaminium halide. Reduction of the formyl moiety in the latter to a methyl function is accomplished by treating this intermediate with a formic acid-formalin mixture at 60° C.-100° C. for 10-24 hours, followed by acidification with the appropriate aqueous hydrogen halide and concentration to dryness yielding a 3-[N'-(3-hydroxypropyl)-N'-methylamino] -N,N,N-trimethyl-1-propanaminium halide hydrohalide. Conversion of this intermediate to 3-[N'-(3-halopropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium halide hydrohalide is accomplished as described in our preferred synthesis of monomer I above, and anion exchange, if desired, is effected by any of the heretofore described procedures.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1([F:26])[CH2:22][CH:21]1[C:23](O)=[O:24]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([CH:21]3[CH2:22][C:20]3([F:26])[F:19])=[O:24])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)C1CC1(F)F
Product: C[C@]1(c2cc(NC(=O)C3CC3(F)F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and (RS)-2,2-difluoro-cyclopropanecarboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=364.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1.[Br-].[K+].Cl[O-].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[C:3](=[O:9])[CH2:2]1
Reactant: OC1COC2OCCC12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1COC2OCCC12
Temperature: -5 °C
Yield: 72 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-ol (55 g) was dissolved in dichloromethane (385 ml) sodium bicarbonate (10%, 165 ml) was added to it and cooled to −5° C. Potassium bromide (2.0 g), 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) (1.0 g) and Tetrabutyl ammonium bromide (1.0 g) was charged to the reaction. Sodium hypochlorite solution (365 ml) was added slowly by maintaining temp 0 to −6° C. Reaction mass was then maintained at 0 to −6° C. for 1 hr. Aqueous layer was separated and extracted with dichloromethane (2×110 ml) combined dichloromethane layers was washed with hydrochloride solution (10%, 110 ml) and Sodium thiosulphate solution (10%, 110 ml). Dichloromethane was then concentrated to residue, the residue was dissolved in isopropyl alcohol (40 ml) & methyl tert-butyl ether (40 ml) and cooled to 0-5° C., and filtered the solid to get the pure solid material of Tetrahydrofuro[2,3-b]furan-3(2H)-one (39 g) having purity 99.18%.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]([CH3:33])=[CH:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]=[C:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)=CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (83 mg, 81%), MS (ISP) m/z=409.4 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][CH2:9][C@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: Cc1cccc(OC[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(OC[C@H](CO)NC(=O)OC(C)(C)C)c1
Reaction time: 48 h
Yield: 104.2 %

Procedure:
To t-butyl (1S)-2-(benzyloxy)-1-[(3-methylphenoxy)methyl]ethylcarbamate (3.8 g) obtained in Step 2 of Example 15 were added 10% palladium-carbon (wet, 1 g) and ethanol (30 ml), and the mixture was stirred for 2 days under hydrogen atmosphere. After celite filtration, the solvent was evaporated. The obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (3.0 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:4].[N+:13]([CH3:16])([O-:15])=[O:14]>CO>[CH2:3]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
An aq. 6 M NaOH solution (1.05 eq) was added to a methonolic solution of 4-ethylbenzaldehyde (1 eq) and nitromethane (1 eq) stirred at 0° C. During the slow addition of base, maintain the temperature between 10-15° C. The reaction generates a thick white precipitate. To allow smooth stirring, an additional amount of MeOH was added. After stirring for an additional 15 min., the ice bath was removed. Upon reaching RT, water was added to the reaction, which subsequently turned clear. The clear solution was added to a flask containing a stirred 6M aq. HCl solution. A yellow crystalline precipitate formed. After 10 min., the crystalline product was filtered, washed thoroughly with water, suction dried and recrystallized from abs. EtOH. 4-ethyl trans-beta-nitrostyrene (2) was afforded as a yellow crystalline product in 52% yield and >99% purity (LC/MS m/z 178.2 MH.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11](Cl)=[C:12]3[C:13](=[O:36])[C:14]4[C:19]([C:6]([C:7]=23)=[N:5]1)=[C:18]([O:20]CC1C=CC=CC=1)[CH:17]=[CH:16][C:15]=4[O:28]CC1C=CC=CC=1.[CH3:38][N:39](CC1C=CC=CC=1)[CH2:40][CH2:41][NH2:42]>>[NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH:42][CH2:41][CH2:40][NH:39][CH3:38])=[C:12]3[C:13](=[O:36])[C:14]4[C:19]([C:6]([C:7]=23)=[N:5]1)=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=4[OH:28]
Reactant: CN(CCN)Cc1ccccc1
Reactant: NCCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(OCc3ccccc3)ccc(OCc3ccccc3)c1-2
Product: CNCCNc1ccc2c3c(nn2CCN)-c2c(O)ccc(O)c2C(=O)c13

Procedure:
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-bis-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one with N-methyl-N-(phenylmethyl)-1,2-ethanediamine as described in Example 78 gives the product; mp 169°-172° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[N:8][C:6]=2[N:7]=1.[CH3:18][N:19]1[C:23]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:22][N:21]=[C:20]1[CH3:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][N:19]1[C:23]([C:24]2[CH:30]=[CH:29][C:27]([NH:28][C:2]3[N:3]=[CH:4][C:5]4[CH:11]=[CH:10][C:9]([C:12]5[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=5)=[N:8][C:6]=4[N:7]=3)=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:22][N:21]=[C:20]1[CH3:33]
Reactant: Cn1cc(-c2ccc3cnc(Cl)nc3n2)cn1
Reactant: COc1cc(-c2cnc(C)n2C)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccc(-c3cnn(C)c3)nc2n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A suspension of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidine (Preparation 55, 7.5 mg, 0.03 mmol), 4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyaniline (Preparation 74, 10 mg, 0.05 mmol), R-(+)BINAP (2 mg, 3 umol), Pd(OAc)2 (0.69 mg, 3 umol), K2CO3 (42 mg, 0.31 mmol) in DMF (3 mL) was stirred at 160° C. under microwave irradiation for 2 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The organic layer was purified by SCX-2 column eluting with 2M NH3 in MeOH and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with 0-10% MeOH in EtOAc followed by preparative HPLC to afford the title compound (4 mg, 31%).
Reaction SMILES: N[C:2]([NH2:4])=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.[N+:29]([C:32]1[CH:37]=[CH:36]C=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(OCC)(=O)C.O.CS(C)=O>[N+:29]([C:32]1[CH:37]=[CH:36][C:2]([NH2:4])=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
A 100 ml three-neck reactor equipped with a condenser and a thermometer was filled with 3.60 g (60 mmol) of urea, 1.50 g of potassium carbonate, 3.96 g (60 mmol) of potassium hydroxide, 0.3034 g of pyrene, and 25 g of DMSO. Then, the resulting mixture was heated to 90° C. while stirring under an oxygen atmosphere. Once the reaction temperature reached 90° C., a mixed solution of 2.48 g (20 mmol) of nitrobenzene and 5 g of DMSO was slowly added dropwise over a period of time of 5 to 10 minutes via a syringe. Then, a temperature was cautioned to keep 90±4° C. while adding a nitrobenzene solution. For a quantitative analysis, a sample was taken out and dissolved in 2.5 ml of ethyl acetate containing a small amount of water, and moisture was then removed from the resulting solution with magnesium sulfate (MgSO4). The quantitative analysis has shown that 4-nitrosoaniline and 4-nitroaniline were obtained in yields of 87 mole % and 12 mole %, respectively, based on nitrobenzene.