Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:17][C@H:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:18][C@H:16]2[CH2:17][C@@H:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:15]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=C([C@H]1C[C@@H](O)C1)N1CCCN(C2CCC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutanol (50 mg, 0.19 mmol) in DCM (2 ml) at RT was added triethylamine (77 mg, 0.7 mmol) and toluene-4-sulfonyl chloride (108 mg, 0.57 mmol). The mixture was stirred at RT for 1 h and then at 35° C. for 2 h. After cooling to RT and dilution with DCM the mixture was washed with 1:1 H2O/saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (73 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:22][CH:21]=[CH2:20])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: C=CCBr
Reactant: Cc1cc2ccc(=O)oc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2oc(=O)ccc2cc1C

Procedure:
A mixture of 6-methyl-7-hydroxycoumarin (I) (14.5 g), anhydrous K2CO3 (5 g), allyl bromide (15 ml) and acetone (400 ml) was refluxed for 12 h under stirring. From the refluxed mixture the solid was filtered and washed several times with acetone. The acetonic solution and the pooled washings were concentrated to dryness and the residue crystallized from MeOH, yielding 6-methyl-7-allyloxycoumarin (IV) (11.4 g; m.p. 124°-5° C.). ##STR9##
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[S:9][C:6]=2[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]1[S:9][C:6]2=[N:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]([Cl:22])=[C:5]2[CH:11]=1
Reactant: COC(=O)CCCc1cc2c(=O)c(C#N)c[nH]c2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cc2c(Cl)c(C#N)cnc2s1

Procedure:
A mixture of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate (136 mg) and 2 drops of N,N-dimethylformamide in 5 mL of phosphorous oxychloride is heated at reflux for 10 minutes and concentrated. To the residue is added dichloromethane and the solution is washed with 1% aqueous sodium bicarbonate solution. The organic layer is dried and concentrated. The residue is purified by flash column chromatography eluting with dichloromethane to provide 126 mg of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester as a tan solid, mp 55-57° C.; 1H NMR (DMSO-d6) δ 1.98 (quintet, J=7 Hz, 2H), 2.42 (t, J=7 Hz, 2H), 3.04 (t, J=7 Hz, 2H), 3.59 (s, 3H), 7.42 (s, 1H), 8.94 (s, 1H); MS 295.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH2:10][C:11]#[N:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC=CC=1C.[CH:21](O)=[O:22]>O>[C:11]([CH2:10][N:9]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH:21]=[O:22])#[N:12]
Reactant: CC(NCC#N)c1ccccc1
Reactant: O=CO
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(c1ccccc1)N(C=O)CC#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a stirred mixture of 104.1 parts of (+)-2-[N-(1-phenylethyl)amino]acetonitrile and 1440 parts of dimethylbenzene are added dropwise 66 parts of formic acid (slightly exothermic reaction). Upon completion, stirring is continued for 3 hours at reflux temperature (water-separator). The reaction mixture is cooled to about 60° C. and washed successively with water, a sodium bicarbonate solution, a diluted sodium hydroxide solution and again twice with water. The organic phase is separated, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding (+)-N-(cyanomethyl)-N-(1-phenylethyl)-formamide (41%); m.p. 78.9° C.; [α] = +60.90° (1% CH3OH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C>O1CCCC1.CCCCCC>[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:23])[OH:21])=[CH:3][CH:4]=1)([OH:14])=[O:13]
Reactant: CC(C)(Cc1ccc(Br)cc1)C(=O)O
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(Cc1ccc(B(O)O)cc1)C(=O)O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1-bromo-4-(2-carboxy-2-methylpropyl)benzene (1.93 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -70° C. A 1.25M solution of n-butyl lithium in hexane (18 ml) was added dropwise with stirring under an argon atmosphere, such that the temperature did not exceed -65° C. After a further 20 minutes, trimethyl borate was slowly added at -65° C. and the reaction mixture was allowed to attain -15° C. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the mixture acidified by the addition of 2M hydrochloric acid. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic phase was washed with brine (15 ml) and evaporated and the residue was triturated with hexane to give 4-(2-carboxy-2-methylpropyl)benzeneboronic acid (1.2 g); 1H NMR (DMSO-d6): 1.06 (s, 6 H), 2.78 (s, 2 H), 7.11 (d, 2 H), 7.67 (d, 2 H), 7.9 (br s, 2 H), 12.2 (br s, 1 H); mass spectrum (-ve ESP) 221 (M-H)-.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(N2CCCC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(N5CCCC5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-pyrrolidin-1-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Phenomenex Luna C18 100A, 10 m silica, 21 mm diameter, 150 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-pyrrolidin-1-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[O:17]1C[CH2:20][CH2:19][CH2:18]1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part B) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of farnesyl chloride (Part A) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether : hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield a yield of 610.5 mg (58%) of pure desired title isomer.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[O:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH-].[Na+]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(Cl)noc2c1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(N3CCNCC3)noc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
3,6-dichlorobenzisoxazole (5.2 g, 27.8 mmol), and anhydrous piperazine (24 g, 278 mmol) are placed in an egg type flask and react at 120° C. for 24 hours. After completion of the reaction, 52 ml of an ice-water mixture is added for quenching the reaction. Further 15 ml of 50% NaOH solution is added to the reaction solution. The reaction solution is stirred for 5 minutes and extracted with dichloromethane (30 ml×3). The dichloromethane layer is combined, washed with 20 ml of saturated saline, dried over anhydrous MgSO4, evaporated to dryness, and subjected to a separation on a column of alumina (200-300 mesh), eluting with dichloromethane:methanol-100:1, to obtain 4.7 g of 6-chloro-3-piperazinyl-benzisoxazole, with a yield of 71%.
Reaction SMILES: C[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.C[CH:11]1[CH2:17][C:16](C)(C)C[C:13](=[O:14])[CH2:12]1>>[CH:17]1[CH:16]=[C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[C:13]([OH:14])=[CH:12][CH:11]=1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: CC1(C)CCCC(=O)C1
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
Following the same procedure as in Example A.2 3 mol of 3,3-dimethylcyclohexanone are used instead of 3 mol of dihydroisophorone. The product had a melting point of 190°-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](Br)=[C:13]([N+:18]([O-])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc([N+](=O)[O-])c(Br)cc2C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Yield: 100.7 %

Procedure:
59 g (0.16 mol) of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinolin-2-carboxylic acid tert-butyl ester, 10 g of 5% palladium on calcium carbonate and 49 g of ammonium acetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for 5 hrs. The reaction was filtered through CELITE®concentrated, basified to pH 12 with 4N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to yield 40 g of an oil.
Reaction SMILES: [CH2:1]([C:10](=O)[C:11]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[CH2:1]([C:10]1[S:33][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][C:11]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)C(=CC(=O)c2ccc(C)cc2)Cc2ccc(OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: COc1ccc(Cc2cc(-c3ccc(C)cc3)sc2Cc2ccc(OC)cc2)cc1
Reaction time: 3.58 h

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 40.6 g (0.105 mole) of 1,2-di-p-anisyl-4-p-tolylbutene-1,4-dione, 100 ml of xylene and 25 g (0.056 mole) of phosphorus pentasulfide. The vessel was chilled with a Dry Ice-acetone bath and charged with 130 g (3.81 moles) of hydrogen sulfide. The autoclave was then heated with stirring for 215 minutes at 158°-165° C. (1250-1360 psig). After cooling the vessel, the hydrogen sulfide was allowed to vent into a sodium hydroxide solution. The residue was treated with 150 ml of absolute ethanol to destroy unreacted phosphorus pentasulfide. After removal of the ethanol there remained 70.5 g of crude product. Recrystallization from ethanol-dioxane (70:30) gave 20 g (49.3%) of pure 2,3-di-p-anisyl-5-p-tolythiophene, m.p. 99°-102° C. and a second crop of 6.5 g (16.0%) m.p. 92°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[C:13]=1[OH:20])=[O:11].[C:21]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[OH:18][C:15]1[C:14]([OH:19])=[C:13]2[C:12]([C:10](=[O:11])[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:21][O:20]2)=[CH:17][CH:16]=1
Reactant: Cc1cc(C)c(Cl)c(C)c1
Reactant: COc1ccccc1CC(=O)c1ccc(O)c(O)c1O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1coc2c(O)c(O)ccc2c1=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
BF3—OEt2 complex (7 ml, 56 mmol) was gradually added to a solution of 2-(2-methoxy-phenyl)-1-(2,3,4-trihydroxy-phenyl)-ethanone (3.8 gm, 14 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (1.5 ml, 42 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 7,8-dihydroxy-3-(2-methoxy-phenyl)-chromen-4-one (0.98 gm, 25%) as white solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:36][CH3:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:28][C:27]([C:22]1[C:21]2[C:20]3[C:19](=[C:32]([CH3:33])[O:31][N:30]=3)[C:18](=[O:34])[N:17]([CH:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:12]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[O:29])[CH3:37]
Reactant: CCI
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1c1noc(C)c1c(=O)n2C1CCCC(CNC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of Example 598, (0.05 g, 0.11 mmol) in DMF (1 ml) under N2 was added iodoethane (0.062 ml, 0.33 mmol) and Cs2CO3 (0.036 g, 0.11 mmol). The mixture was stirred overnight, diluted with EtOAc, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, acetone/dichloromethane gradient) gave the title compound (0.043 g, 80%). MS(FIA) (m/z) 488.4 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1cccc(Cl)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 39.9 %

Procedure:
Example 8 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3-chlorophenyl)acetic acid (0.034 g) to give thetitle compound (0.034 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(N(CC)CC)C>ClCCl>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:7](=[O:8])[C:6]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])=[CH:31][C:32]=1[C:38]([F:39])([F:40])[F:41])#[N:35]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Propoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-n-propoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH:11]=[O:12].[BH4-].[Na+]>CO>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH2:11][OH:12]
Reactant: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To form 2,3-dichloro-6-nitrobenzylalcohol (compound XX) from 2,3-dichloro-6-nitro benzaldehyde (compound XIX), compound XIX is preferably solubilized in a solvent or solvent mixture such as toluene and methanol. The solution of compound XIX is added to a reducing solution such as sodium borohydride in an organic solvent over a period of time to maintain a reaction temperature below about 40° C., preferably 25° C. The reaction is preferably stirred for 24 hours at room temperature under nitrogen and then washed with water. After removing the aqueous layer the organic layer is azeotropically dried and concentrated forming 2,3-dichloro-6-nitrobenzylalcohol (compound XX).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23]>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])[CH:29]=1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound in Example 36, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (115 mg, 4.02 mmol) and 3-methoxycarbonyl phenylboronic acid (145 mg, 8.04 mmol) in 1,4-dioxane (5 mL) is treated with copper(II) acetate (110 mg, 6.03 mmol) and CS2CO3 (262 mg, 8.04 mmol). The mixture is stirred at RT for 16 h and the solvent is evaporated. The residue is partitioned between EtOAc and 1N aqueous HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated. The residue is flash chromatographed on silica gel using 30% EtOAc in hexanes as the eluent to give 3-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]benzoic acid methyl ester as a clear oil: [M+NH4]+=438.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:48]1([C:17]([C:16]2[N:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=23)=[O:19])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), morpholine (174 mg, 2 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 20b (400 mg, yield 100.0%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][C:23](Cl)=[O:24]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:23](=[O:24])[CH2:22][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Product: CCOC(=O)c1cc(C(=O)Cc2ccc3ccccc3c2)c(C)[nH]1

Procedure:
5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethyl ester (135) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and naphthalen-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 80%.