Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:3]1>CO.[Pd]>[CH3:1][C@:2]1([NH2:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: C[C@]1(NC(=O)OCc2ccccc2)CCCN(c2ccc(C(F)(F)F)cc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@]1(N)CCCN(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of (S)-benzyl (3-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate (2.05 g, 5.22 mmol) in MeOH (20 mL) was added palladium on carbon (0.406 g, 3.81 mmol) under nitrogen atmosphere. The resultant black color suspension was stirred under hydrogen balloon pressure at rt for 2 hours. The reaction mass was filtered on Celite, the filter cake was washed with methanol (3×10 mL), and combined filtrate was concentrated and dried under vacuum to get 1.6 g of crude compound. This crude was purified on a 12 g silica cartridge by ISCO, eluted the compound around 5% methanol in chloroform. Pure fractions were collected and concentrated to get (S)-3-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-3-amine (570 mg, 1.493 mmol, 28.6% yield) as pale yellow gummy solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[OH-].[Na+].O.Cl>C(O)C>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc(Cl)c2ccccc2c1O
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 9.23 g of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (33 mmol), 90 ml of 2.5N aqueous sodium hydroxide solution, water (20 ml) and ethanol (110 ml) was refluxed with stirring for 2 h. Then the pH of the mixture was adjusted to 2 by the addition of concentrated aqueous hydrochloric acid. During the addition, the temperature of the mixture was kept at 20° C. by cooling with an ice bath. Stirring was then continued for 1 h before the solid component was separated by vacuum filtration. The filter cake was washed with water and dried in vacuo at 85° C. to give a white powder. 6.64 g of the title compound were obtained; MS-(+)-ion: M+1=224.1 amu.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1.[C:26]([Li])(C)(C)C.CI>>[C:22]([Si:19]([CH3:21])([CH3:20])[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:6]=2)[C:2]([CH3:26])=[CH:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1
Reactant: [Li]C(C)(C)C
Solvent: CI
Product: Cc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12

Procedure:
In analogy to the procedure described in example 27 c], 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole was treated with tert-butyllithium and methyl iodide to yield 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indole as red crystals.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:14]=[C:15](O)[C:16]4[S:21][CH2:20][CH2:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:15]1[C:16]2[S:21][CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Product: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Temperature: 120 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
4.3 g (13.7 mmol) of 2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (IV) and 25 mL of phosphorus oxychloride are combined and stirred for 5 hours at 120° C. Excess phosphorus oxychloride is concentrated by evaporation, the residue is combined with ice water and dichloromethane. The organic phase is separated off and evaporated to dryness. The residue is triturated with water, suction filtered, and dried. 5.6 g of the product (100%) is obtained as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH:13]1[C:21]([O:23]C)=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH:13]1[C:21]([OH:23])=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In a 50 mL round-bottomed flask, methyl 1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (660 mg, 1.58 mmol, Eq: 1.00) was combined with THF (14.8 mL) and methanol (4.95 mL) to give a colorless solution. The solution was cooled in an ice-bath and 1 M aqueous lithium hydroxide (4.74 mL, 4.74 mmol, Eq: 3) was added. The cooling bath was removed and the reaction was stirred at rt for 1 h. 0.1 M Aqueous KHSO4 (4 mL) was added and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid as a white solid (600 mg), m/z=404 (M+H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]2[C:5]([CH2:6][C:7]3([C:20]2=[O:23])[CH2:18][C:17]2[C:19]4[C:13]([CH:14]=[CH:15][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=4[CH2:8]3)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:23]=[C:20]1[C:7]2([CH2:8][C:9]3[C:19]4[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18]2)[CH2:6][C:5]2[C:21]1=[CH:22][C:2]([C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[C:24]#[N:25])=[CH:3][CH:4]=2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12Cc1cccc3cccc(c13)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(C3)Cc3cccc4cccc(c34)C2)c1
Temperature: 100 °C
Yield: 59.2 %

Procedure:
6-Bromo-1′,3′-dihydrospiro[indene-2,2′-phenalen]-1(3H)-one (200 mg, 0.57 mmol) and 3-cyanophenylboronic acid (168 mg, 1.17 mmol) was dissolved in 1,4-dioxane (5 mL), Cs2CO3 (0.6 mL, 2 M) was added. Then Pd(PPh3)2Cl2 (10 mg) was added under N2. The mixture was heated at 100° C. for 10 minutes under microwave. The solvent was removed in vacuum. The crude product was purified by preparative TLC to give 3-(1-oxo-1,1′,3,3′-tetrahydrospiro[indene-2,2′-phenalene]-6-yl)benzonitrile (130 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH:24]([Si:27]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1)([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:30]3[CH:31]=[CH:32][N:28]([Si:27]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:24]([CH3:25])[CH3:26])[CH:29]=3)=[CH:17][C:9]1=2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Yield: 80 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (111 mg) was reacted with 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid as in General Procedure 4B to give the title compound as an off-white solid (80% yield). LCMS: m/z=349.34 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.08 (18H, d, J=7.6 Hz), 1.41 (3H, m), 3.49 (2H, m), 3.65 (2H, m), 4.58 (2H, s), 4.92 (1H, bs), 6.37 (1H, m), 6.54 (1H, d, J=1.8 Hz), 6.72 (1H, m), 6.76 (1H, m), 7.32 (1H, d, J=8.6 Hz), 7.54 (1H, s), 7.61 (1H, d, J=8.6 Hz), 7.70 (1H, m).
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:13][CH2:14]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of 6.02 g (17.43 mmol) of trans-Methanesulfonic acid 3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-prop-2-ynyl ester in 95 ml CH2Cl2 was treated at 0° C. with 45 ml TFA (for 20 min). After 30 min at this temperature, the reaction was evaporated and evaporated again with toluene (4 times) to give 8.17 g (quantitative) of crude trans-Methanesulfonic acid 3-(4-methylamino-cyclohexyl)-prop-2-ynyl ester.trifluoroacetate, MS: 245 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]#[N:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:26][N:25]=[N:24][N:22]=3)[C:9]=2[CH3:23])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (500 mg, 1.39 mmol), sodium azide (1.08 g, 16.6 mmol) and ammonium chloride (890 mg, 16.6 mmol) dissolved in dimethylformamide (3 ml) was placed in a microwave synthesizer tube, and subjected to microwave irradiation in a Biotage® Initiator was set at 180° C. After 20 minutes, the mixture was quenched with water and extracted with ethyl acetate. The solvent of the extracted organic layer was evaporated off and the residue was purified by reverse phase preparative HPLC, to obtain 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (550 mg, 98%) as white solid.
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:36])[C:14](=[CH:32][N:33]([CH3:35])[CH3:34])[C:15]2[O:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.Cl>C1COCC1>[OH:6][C:7]1[CH:8]=[C:9]([C:13](=[O:36])[C:14](=[CH:32][N:33]([CH3:35])[CH3:34])[C:15]2[O:16][C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=C(C(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C=C(C(=O)c1cccc(O)c1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 95.7 %

Procedure:
The 1-[3-[(1,1-dimethylethyl)dimethylsiloxy]phenyl]-2-[(dimethylamino)methylene]-2-(4,5-diphenyl-2-oxazolyl)ethanone (19) (10.3 g, 19.6 mmol) was dissolved in THF (100 mL) and tetra-n-butyl ammonium fluoride (17.5 mL of 1M in THF) was added dropwise. The reaction mixture was stirred for about 1/4 hour and poured onto an ether (180 mL)/1N HCl(20 mL) solution, and the organic phase separated and dried (MgSO4). Chromatography (elution with 75% ethyl acetate/hexanes) gave the phenol 7.7 g (96%). IR (KBr, cm-1) 3170, 3060, 2920, 1735, 1635, 1600, 1447, 1375, 1310, 1210, 1010, 965, 870, 765, 695. 1H NMR (300 MHz, CDCl3) δ 2.6 to 3.1 (6H, Series of Br. s) 6.84 (1H, Br.s), 6.95 (1H, Br. s), 7.04 to 7.24 (10H, m), 7.32 to 7.60 (5H, m). m/e 411 (MH+)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]N1C(=O)CCC1=O)=O.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)=[O:10]
Reactant: O=C(CN1CCCC1=O)ON1C(=O)CCC1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1CCCC1=O)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 14.4 g (60 mmol) of N-[2-(2-oxopyrrolidin-1-yl)-acetoxy]-succinimide and 10.6 g (60 mmol) of 1-benzylpiperazine in 125 ml of dimethylformamide is stirred for 16 hours at 20°. The reaction mixture is concentrated to dryness by evaporation under reduced pressure at 90°. The oily residue is taken up in 250 ml of water, and a solution of 5.4 g of oxalic acid in 5 ml of water is added, and then the whole is stirred in an ice bath. The resulting crystalline oxalate is filtered off with suction, dissolved in 400 ml of water and the pH is adjusted to 9 with concentrated ammonia solution The clear aqueous solution is washed twice with 30 ml of ether each time, the ethereal extracts are discarded and the aqueous layer is concentrated by evaporation under reduced pressure at 70°. The residue is composed of a sticky mass which is stirred into 400 ml of ethanol at 30° and the insoluble matter is filtered off with suction. After concentrating the clear ethanolic filtrate by evaporation, a slightly yellowish oil is obtained. This is boiled in 130 ml of ethyl acetate and filtered while hot, and the filtrate is stirred in an ice bath to complete the reaction. The precipitated crystals are filtered off with suction and dried on a water bath. 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]-4-benzylpiperazine is obtained.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Reactant: COc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCn1c(SCc2cccc(OC)c2)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.075 g, 0.222 mmol), 3-methoxybenzyl bromide (0.034 ml, 0.244 mmol), potassium hydroxide (0.019 g, 0.332 mmol) in Ethanol (1.303 ml) was refluxed overnight. To the cooled solution, water (1 ml) was added and the product was extracted with 10% MeOH in EtOAc, dried over sodium sulfate, and concentrated. The title compound was purified by flash column chromatography, eluting with 0 to 5% EtOAc in hexane. 1H NMR (500 MHz, CDCl3) δ ppm 8.15, 7.38-7.23, 7.06-7.02, 6.86-6.84, 5.945.32, 5.32-5.27, 4.69, 4.59, 3.77, 3.06, 2.60, 1.75-1.72, 1.60-1.54, 1.43-1.37; MS (EI) m/z 459 (M+1)
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1.C([Li])CCC.[C:36](=[O:38])=[O:37].Cl>O1CCCC1>[CH2:23]([C:5]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]2[CH:3]=[C:2]([C:36]([OH:38])=[O:37])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Into a flask fitted with a nitrogen inlet and rubber septum were introduced 2-bromo-9,9-dioctylfluorene (34.18 g, 72.8 mmole) and dry tetrahydrofuran (300 mL). The solution was cooled to −60° C. and n-butyl lithium (29.1 mL, 2.5M in hexanes, 72.8 mmole) added via a syringe. The reaction mixture was observed to turn red. After stirring for 1 hour at −60° C., the reaction mixture was poured onto powdered dry-ice and left to stand overnight. The mixture was acidified with 1M HCl and extracted with chloroform. The chloroform extract was washed with water, dried over magnesium sulfate and concentrated to give the required acid as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Br>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:28][CH:30]2[O:32][CH2:31]2)[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC1CO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
A mixture comprising 2 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 20 ml of dimethylformamide, 1.4 g of potassium carbonate and 1.4 g of epibromohydrin, was stirred at 60° C. overnight. After distilling off the solvent under reduced pressure, the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed sequentially with an aqueous potassium carbonate solution and with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 2.6 g of the above-identified compound as oily substance.
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.I([O-])(=O)(=O)=[O:20].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
7.6 gm (0.003 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and 13.75 gm (0.03 mol) of tetrabutylammonium periodate (prepared from tetrabutylammonium hydrogen sulfate and sodium metaperiodate in water) in 50 ml of dichloromethane were refluxed for about 2 hours. After the end of the reaction, which was monitored by thin-layer chromatography, the mixture was allowed to cool and was then filtered through a column of silicagel (200 gm), finally using dichloromethane/ethyl acetate (97:3 v/v) as the eluant. By evaporating the appropriate fractions and subsequently recrystallizing the residue from ethanol, 5.8 gm (72% of theory) of pale yellow crystals, m.p. 246°-247° C. (decomposition), were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
To a stirred mixture of 2-hydroxy-4-nitrobenzonitrile (4 g, 24.37 mmol) and cesium carbonate (11.91 g, 36.6 mmol) in DMF (40 mL) was added tert-butyl 3-bromopropylcarbamate (8.71 g, 36.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in ethyl acetate (250 mL), washed with brine (2×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give tert-butyl 3-(2-cyano-5-nitrophenoxy)propylcarbamate (5 g, 63.8%) as a yellow solid. LC-MS (M+H)+=321.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.89-7.87 (1H, m), 7.81 (1H, s), 7.75 (1H, d, J=8.4 Hz), 4.76 (1H, br s), 4.27-4.24 (2H, t, J=6.4 Hz), 3.40-3.36 (2H, q, J=6.4, 12.8 Hz), 2.15-2.09 (2H, m), 1.43 (9H, s).
Reaction SMILES: [Al](C)(C)C.[CH3:5]NCCNC.CO[C:13](=[O:27])[C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[C:16]([C:25]#[N:26])[CH:15]=1.Cl>C1(C)C=CC=CC=1>[C:13]([C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:17]=[C:16]([C:25]#[N:26])[CH:15]=1)(=[O:27])[CH3:5]
Reactant: CNCCNC
Reactant: COC(=O)c1cc(C#N)cc(NS(C)(=O)=O)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C#N)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Al(CH3)3 (20 mmol) was added dropwise to the ice-water cooled solution of DMEDA (4.4 mmol) in dry toluene (60 mL) under nitrogen. After addition, it was continued to stir for 2 hours at room temperature. Then, methyl-3-cyano-5-(methylsulfonamido)benzoate (4 mmol) was added, and the reaction mixture was heated to reflux overnight. After cooling, it was poured into diluted hydrochloric acid, the mixture was extracted with EtOAc, the combined organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-acetyl-5-cyanophenyl)methanesulfonamide with a yield of 35%. Br2 (1.2 mmol) was added dropwise to the solution of N-(3-acetyl-5-cyanophenyl)methanesulfonamide (1 mmol) in Et2O (50 mL). After addition, it was continued to stir for 1.5 hours. Then the reaction mixture was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide with a yield of 85%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1cccc(Cl)c1
Product: COc1ccc2c(-c3cccc(Cl)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-chloro-phenylboronic acid to give [1-(3-chloro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).