Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]=[N+:10]=[N-:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1COCC1>[CH2:1]([N:9]1[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:19][N:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CCn2nncc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
Phenethyl azide (148 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (8 mg, 0.01 mmol, 1 mol %). Solvent: THF, 10 mL, 60° C., 2 hours. Off-white product obtained in 89% yield (221 mg). ESI-MS: m/z 250, [M+H].
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].[SH:16][CH2:17][CH2:18]O.OO>>[CH3:5][C:3]1[O:4][CH2:18][CH2:17][S:16][C:2]=1[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: OCCS
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(C(=O)Nc2ccccc2)SCCO1
Temperature: 38 °C
Yield: 68.1 %

Procedure:
Acetoacetanilide (88.6 g, 0.5 mole) is dissolved under agitation, at room temperature, in 140 g aqueous 28.6% NaOH (0.5 mole). Crude di-(2-hydroxyethyl) disulfide (176 g), obtained by oxidation of 2-mercaptoethanol with 50% hydrogen peroxide, (i.e. an approx 68% aqueous solution) is added to the reaction mixture, which is then heated to 38° C. After 15 minutes 15% aqueous NaOH (16 g) is added and after a further 15 minutes the addition of 50% hydrogen peroxide is started. Subsequently the reaction is carried out as described in EXAMPLE 1. A total of 16.8 g 50% hydrogen peroxide is used. The extraction/acidification procedure, as well as the cyclization step, is carried out as in EXAMPLE 1. After the last water wash, following the cyclization, toluene is evaporated from the reaction mixture under vacuum, at up to 60°, and the residue is redissolved in 90 g isopropanol. After crystallization, filtration and drying, 80.2 g 5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide is obtained (yield 68.1% based on acetoacetanilide), M.P. 96.8°-98.0° C., Assay 98.9%.
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1[C:5]([CH2:16][Si](C)(C)C)(O)[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]2[C:12]=1[O:11][CH2:10][O:9]2.O>O1CCCC1>[CH3:3][C:4]1[C:5](=[CH2:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]2[C:12]=1[O:11][CH2:10][O:9]2
Reactant: CC1=C2OCOC2CC(C)(C)C1(O)C[Si](C)(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C(C)=C2OCOC2CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
23 ml (about 1 eq.) of potassium hydride (20% in oil) were placed in a 750 four-necked sulphonation flask provided with a magnetic stirrer, dropping funnel and argon gasification, washed three times with hexane and 120 ml of tetrahydrofuran were added. A solution of 30.4 g (0.11 mol) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-trimethylsilylmethyl-1,3-benzodioxol-5-ol in 200 ml of tetrahydrofuran was added dropwise thereto at 0° C. Subsequently, the suspension was stirred at 20-30° C. for 2 hours. It was again cooled to 0° C. and 200 ml of water were cautiously added dropwise. Subsequent three-fold extraction with 100 ml of hexane each time, washing with saturated sodium chloride solution and drying over anhydrous sodium sulphate gave, after removal of the solvent under reduced pressure, 18.7 g of yellow oil which was subjected to short path distillation under reduced pressure. At 77-85° C./0.75 mbar (7.5 kPa) there were obtained 15.6 g (74% yield) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-methylidene-1,3-benzodioxol as a colorless oil. The content of desired product was 96% according to GC (area %). IR (film, cm−1): 1697, 1600; mass spectrum: 180 (M+, 50), 107 (100); 1H-NMR (C6D6, 400 MHz): inter alia 0.83 and 0.95 (2s, in each case 3H), 1.78 (bs, 3H), 3.9 (m, 1H), 4.59 (s, 1H), 4.70 (s, 1H), 4.75 (s, 1H), 4.91 (s 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]4[C:18]([CH3:21])=[N:19][N:20]=[C:13]4[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=[C:9]2[S:27][CH3:28])=CC=1.FC(F)(F)C(O)=O>>[CH3:21][C:18]1[N:14]2[C:15](=[O:17])[C:16]3[NH:8][C:9]([S:27][CH3:28])=[N:10][C:11]=3[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:20][N:19]=1
Reactant: CCCCCn1c2nc(SC)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc(SC)[nH]c2c(=O)n2c(C)nnc12
Yield: 0 %

Procedure:
A solution of 6-(4-methoxybenzyl)-3-methyl-7-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 469 mmol) in trifluoroacetic acid (5 ml, 64.9 mmol) was stirred at 55° C. overnight. The solution was concentrated and purified by prep LCMS to yield the desired product (60 mg, 42%). 1HNMR (300 MHz, CD3OD): δ 4.42 (t, J=7.5 Hz, 2H), 2.74 (s, 3H), 2.45 (s, 3H), 1.92 (m, 2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated for C13H19N6OS (M+H): 307.1. Found 307.1.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12]CC)=O.Cl[CH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[O:12]=[C:10]1[CH:9]([C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:20][C:21](=[O:22])[NH:23]1
Reactant: NC(=O)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NC1=O
Reaction time: 20 h
Yield: 65.4 %

Procedure:
To a solution of 20% sodium ethoxide-ethanol solution (34.0 g) diluted with ethanol (40 ml) was added a solution of diethyl malonate (16.0 g) in ethanol (40 ml) dropwise over 30 minutes in ice-cooling. After stirring in ice-cooling for additional 30 minutes, thereto was added 2-chloroacetamide (4.7 g) in one portion and the mixture was stirred in ice-cooling for 30 minutes and then at room temperature for 20 hours. The white solid precipitated was collected by filtering and washed with a small amount of ethanol. This white solid was dissolved in water (300 ml) and this resulting aqueous solution was acidified with conc. hydrochloric acid and extracted with dichloromethane (50 ml) three times. The extract was dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This was purified by a flash column chromatography (n-hexane:ethyl acetate=2:1→1:1) to give ethyl 2,5-dioxopyrrolidine-3-carboxylate (5.63 g, 66%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].[H-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CN(C=O)C>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:14][CH2:13]3)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1CCc2cc(OCc3ccc(Br)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (5.0 g; obtained in Reference Example 16) was dissolved in DMF (130 ml), to which was added 60% oily sodium hydride (1.46 g) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 1 hour. This was again cooled to 0° C., to which was added a DMF solution (20 ml) of 4-bromobenzyl bromide (10.0 g). The reaction mixture was stirred at room temperature for 2 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (3.4 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1

Procedure:
2-(4-ethylphenoxy)-5-nitropyridine (7.33 g, 30 mmol) was dissolved in carbon tetrachloride (100 mL), and to the resulting solution were added N-bromosuccimide (5.34 g, 30 mmol) and benzoyl peroxide (0.73 g, 3 mmol). This solution was refluxed overnight under a nitrogen atmosphere. The reaction solution was allowed to cool, after which insoluble matter was removed by filtration. The resulting filtrate was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.34 g of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([NH2:31])([CH3:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([NH:31][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])([CH3:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC1(N)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(Nc2ccccc2[N+](=O)[O-])CCN(Cc2ccccc2)CC1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
3.6 g 1-fluor-2-nitrobenzene and 82.7 g potassiumcarbonate were added to 5.3 g 1-benzyl-4-methyl-piperidin-4-ylamine in 50 mL DMSO and the mixture was stirred at 150° C. 24 h. The reaction was diluted with water and the aqueous layer was extracted with ethylacetate. The organic layer was evaporated and the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1) to give 5.9 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[O:8][N:9]=[C:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:8][N:9]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Oc1noc2nc(Cl)ccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Product: CC1CCN(C(=O)Oc2noc3nc(Cl)ccc23)CC1

Procedure:
In analogy to example 1, 55 mg (0.32 mmol) of 6-chloroisoxazolo[5,4-b]pyridin-3-ol were reacted with 62.7 mg (0.39 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 22 mg (24%), M+H+: 296.04.
Reaction SMILES: [H-].[Na+].[N:3]1[N:12]2[C:6]([CH2:7][O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11]2)=[CH:5][C:4]=1[CH2:17][OH:18].C[N+]1([O-])CCOCC1.C(#N)C>CN(P(N(C)C)(N(C)C)=O)C.C1(C)C=CC=CC=1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH:3]1[N:12]2[C:6](=[CH:7][O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11]2)[CH:5]=[C:4]1[CH:17]=[O:18]
Reactant: OCc1cc2n(n1)Cc1ccccc1OC2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: O=CC1=CC2=COc3ccccc3CN2N1
Temperature: 95 °C

Procedure:
The diol compound (3.83 g, 16.21 mmol) in HMPA (24 ml) was added to a suspension of NaH (60%, 1.34 g, 33.5 mmol) in toluene (330 ml) under N2. Rapidly heated to 95° C. for three hours and cooled to room temperature. Quenched with water and extracted with EtOAc. Washed organics with water and brine. Dried organics over sodium sulfate and filtered and concentrated. Purified with silica gel column and 2% MeOH in CH2Cl2. Obtained 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol (white solid). Yield: 0.71 g 20%. 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol (0.71 g, 3.28 mmol), 4-methylmorpholine N-oxide (1/198 g, 10.23 mmol), molecular sieves (powder, 4 angstroms) (3.32 g), and acetonitrile (0.07M) were placed together under N2. Tetrapropylammoniumperruthenate (0.113 g, 0.322 mmol) was added and after three hours the reaction solution was filtered through celite and concentrated. Purified with silica gel column and 1:1 EtOAc/Hexane. Obtained 4H, 10H-pyrazolo[5,1-c][1,4]benzoxazepine-2-carbaldehyde (white solid). Yield: 0.31 g 44%.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:9].[CH2:10]([OH:12])[CH3:11]>C(Cl)(Cl)Cl>[ClH:9].[CH2:10]([O:12][C:1](=[NH:2])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:11]
Reactant: CCOC(=O)CC#N
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-cyanoacetate (100 mL, 94 mmol) in chloroform (100 mL) and ethanol (6.5 mL) is bubbled with HCl at −10° for 4 h. The reaction mixture is allowed to warm to RT slowly and then stirred at RT overnight. The mixture is concentrated in vacuo to remove the solvent. The residue is suspended in diethyl ether (100 mL) and stirred for 30 min. The resulting solid is collected by filtration and rinsed with diethyl ether to afford ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-1) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=C1.[CH3:27][S:28]N1C(=O)C2C(=CC=CC=2)C1=O.[Br-].[Mg+2].[Br-].[OH-].[Na+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:28][CH3:27])=[CH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ccc3ccccc32)cc1
Reactant: CSN1C(=O)c2ccccc2C1=O
Agent: [Br-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cc(SC)c3ccccc32)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
1-(4-methoxyphenyl)-1H-indole (synthesised from indole by an arylation process analogous to that described in step (a) of Example 1 [arylation process also described in J. Org. Chem. 2008, 73 (14), 5529-5535], 1.0 g, 4.48 mmol), 2-(methylthio)isoindoline-1,3-dione (0.95 g, 4.93 mmol) and magnesium bromide (8 mg, 0.045 mmol) were mixed in degassed DMA and stirred under an atmosphere of nitrogen at 90° C. for 90 min. 1M NaOH and EtOAc were added. The phases were separated and the organic solvents were evaporated. The residue was purified by flash chromatography with heptane/EtAc 20:1 to provide 1-(4-methoxyphenyl)-3-(methylthio)-1H-indole in 80% yield. ES/MS m/z: 270.11 (M+H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1[N:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:14][C:15]=1[CH2:16][CH2:17]O.[OH-].[Na+]>O>[CH3:10][C:11]1[N:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:14][C:15]=1[CH2:16][CH2:17][O:2][N+:1]([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(-c2cccnc2)sc1CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cccnc2)sc1CCO[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
3-[4-Methyl-5-(2-nitrooxy-ethyl)-thiazole-2-yl]-pyridine was prepared by drop-wise addition of 1.145 gr. of nitric acid (70%) to 1.78 grams of cooled sulfuric acid (95-98%) at 0-5° C., followed by addition of 4 grams (0.0181 moles) 2-(4-methyl-2-pyridin-3-yl-thiazole-5-yl)-ethanol over a time period of 30 minutes at 0-5° C. After the addition was completed the reaction mixture was stirred for 30 minutes at 0-5° C., and for one additional hour at room temperature. The reaction mixture was then added carefully to 25 ml of cold water. The water solution was turned basic with an aqueous 20% solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The nitration step was confirmed initially by thin-layer chromatography stained with diphenylamine as a marker for the nitrate ester moiety (FIG. 1). Chromatography of the crude product on silica gel (using ethyl acetate as eluent) gave 1.5 grams (41% yield) of Pet-12 as a pale yellow liquid having a purity of 99% as determined by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[NH2:10][CH2:9][C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14]
Reactant: CN(C)CCOc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cccc(CN)c1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
3-(2-Dimethylamino-ethoxy)-benzonitrile (0.8 g, 1 eq, 4.1 mmol) was dissolved in THF (80 mL) and cooled down to 0-5° C. A 1.0 M solution of lithium aluminium hydride in THF (0.47 g, 3.0 eq, 12.3 mmol) was added at 0-5° C. The reaction mixture was allowed to warm to RT and was stirred for 4 hrs. After completion of the reaction (confirmed by TLC), ethyl acetate at 0-5° C. was slowly added to quench any excess of lithium aluminium hydride in the reaction mixture, followed by addition of saturated sodium sulphate solution (2 mL). The reaction mass was filtered through hy-flow bed and the filtrate was concentrated in vacuo to obtain the crude product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:13]1[C:12](=[O:32])[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[C:14]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.53 g (7.39 mmol) of tert-Butyl 4-(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butylcarbamate are dissolved in 150 ml of dichloromethane, and a solution of 10 ml of trifluoroacetic acid in 50 ml of dichloromethane is added at 0° C. The reaction mixture is slowly warmed to RT and stirred overnight. The reaction mixture is then concentrated and the oily residue is stored at 5° C. overnight. Dichloromethane and a little ethanol are added to the residue, which is now partially crystalline, and the mixture is filtered. This gives 3.44 g (95% of theory) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)/[CH3:24]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=[C:26]2[CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(=O)CCCOc1cccc(F)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(CCCOc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.36 g, 1.83 mmol) in DCM (20 mL) was added trimethylaluminium (2.7 mL, 5.40 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(4-(3-fluorophenoxy)butanamido)but-2-enoate (0.80 g, 2.71 mmol) in DCM (4 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow solid (0.40 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])C.[Li+].[OH-]>C1COCC1.O>[CH3:20][C:5](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])[C:4]([OH:21])=[O:3]
Reactant: CCCc1cc(C(F)(F)F)ccc1C=C(C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(C(F)(F)F)ccc1C=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a suspension of 2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid ethyl ester (68 mg, 0.23 mmol) in THF (1 mL) was added a solution of 1N-LiOH (10 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1-2. The solution was extracted three times with methylene chloride and then dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound (60 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:46])[CH:43]([CH3:45])[CH3:44].O>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])[C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C(=O)C(C)C)c1ncc(Br)cn1
Yield: 51.7 %

Procedure:
In a solution of 1.5 g of N-(5-bromo-2-pyrimidinyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl benzoic acid amide, 0.42 g of triethylamine and 0.03 g of 4-(dimethylamino)pyridine in 50 mL of tetrahydrofuran, 0.42 g of isobutyryl chloride was added at room temperature with stirring and stirred at the same temperature for 18 hours. After the completion of the reaction, 50 mL of water was added in the reaction mixture, extracted with ethyl acetate (80 mL×1), 5 g of silica gel was added in the organic phase, stirred and filtered off, and then the solvent was distilled off under reduced pressure. The residue was subjected to crystallization from diethyl ether and hexane to obtain 0.87 g of the aimed product as white crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCCCCCCCCCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 128 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-bromodecane and conditions outlined in procedure V. M.p.=110-111° C.; 400 MHz 1H NMR (CDCl3) δ 8.06 (d, J=1.2 Hz, 1H), 7.8-7.75 (m, 1H), 7.75-7.6 (m, 1H), 7.53-7.43 (m, 1H), 2.93 (s, 2H) 2.85-2.75 (m, 2H), 2.5-2.35 (m, 4H), 2.2-2.05 (m, 2H), 1.95-1.8 (m, 2H), 1.6-1.43 (m, 2H), 1.4-1.18 (m, 14H), 0.9-0.8 (m, 3H); LCMS: 442 [M+H].