Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH:20]([NH:22][CH:23]3[C:32]4[C:27](=[C:28]([OH:33])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH3:21])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C=O)C>[C:3]1([C:9]2[N:10]=[C:11]([CH:20]([NH:22][CH:23]3[C:32]4[C:27](=[C:28]([O:33][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH3:21])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: CC(NC1CCCc2c(O)cccc21)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 57.1 %

Procedure:
A solution of NaH (60% oil, 66 mg) and 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.55 g) in DMF (10 ml) was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl bromoacetate (0.26 g). After being stirred for 7 hours at room temperature, the solution was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.38 g).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2].C1CN([P+](ON2N=[N:49][C:44]3[CH:45]=[CH:46][CH:47]=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(CN)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:45]1([CH2:44][NH:49][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([S:13]([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5]3)(=[O:14])=[O:15])=[CH:17][CH:18]=2)[CH2:47][CH2:46]1
Reactant: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)O)cc2)c2ccccc12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)NCC3CC3)cc2)c2ccccc12
Yield: 87.1 %

Procedure:
Stir mixture of 4-(3-isopropyl-indole-1-sulfonyl)-benzoic acid (0.181 g, 0.53 mmol), PyBOP (0.243 g, 0.55 mmol) and cyclopropylmethyl amine (0.064 g, 0.59 mmol) in CH2Cl2 (20 mL) add Hunigs base (0.28 mL, 1.62 mmol) under N2. Stir the resulting mixture overnight at ambient temperature. Extract the reaction with H2O, wash with brine dry (MgSO4), filter, evaporate and chromatograph using hexane-EtOAc (0-100%) to give 0.183 g of the title compound as an off white solid: Mass spectrum (m/e) (M+H) 397.1593; found 397.1586.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][N:6]=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1([C:44]([O:46][CH3:47])=[O:45])[CH2:43][CH2:42][CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.[Cu]I.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>[CH3:47][O:46][C:44]([C:40]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:2]#[C:1][C:3]2[C:8]([C:9]([F:10])([F:12])[F:11])=[CH:7][N:6]=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:4]=2)[CH2:43][CH2:42][CH2:41]1)=[O:45]
Reactant: COC(=O)C1(c2ccccc2I)CCC1
Reactant: C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1

Procedure:
A suspension of tert-butyl 4-(4-((4-ethynyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A51 (169 mg, 0.380 mmol), methyl 1-(2-iodophenyl)cyclobutanecarboxylate A53 (100 mg, 0.316 mmol), PPh3 (8 mg, 0.03 mmol) and CuI (3 mg, 0.02 mmol) in DMF (3 mL) and Et3N (0.5 mL) was sonicated for 10 minutes before PdCl2(PPh3)2 (22 mg, 0.032 mmol) was added. The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes, adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C. (column run twice)) to give the title compound A54 as a yellow oil (33 mg, 16%). LCMS-A: rt 7.919 min; m/z 635 [M+H]+.
Reaction SMILES: [Br-:1].[Na+].CN(C=O)C.S([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)([O-])(=O)=O>O>[Br:1][CH2:13][CH2:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:12][CH2:17][CH2:18][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCC(C)CCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (20 ml) was added to a methylene chloride (50 ml) solution of the 3-methyldodecan-1-ol (4″) (12.8 g, 63.9 mols), and p-toluenesulfonyl chloride (12.8 g, 67.1 mmols) was further added under ice-cooling. The reaction mixture was stirred overnight at 4° C., then poured into diluted hydrochloric acid, and extracted with hexane. The organic layer was washed (water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure to obtain 21.7 g of a tosylate. Sodium bromide (9.9 g, 96 mols) was added to a DMF solution (100 ml) of the resulting tosylate, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and extracted with hexane. The organic layer was washed (water and a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure to obtain 1-bromo-3-methyldodecane (5″) (15.1 g, 90%). 1H-NMR (90 MHz, CDCl3) 0.8-1.0 (6H,m,Me), 1.0-2.0 (19H,m,2˜11-H), 3.43 (2H,br t,J=7,1-H).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[C:5]1=[O:26])(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:6]2[NH:7][C:8](=[O:10])[C:9](=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:4][C:5]2=[O:26])=[N:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccc(OCc3ccccc3)cn2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=Cc1ccccc1
Temperature: 60 °C
Yield: 83 %

Procedure:
Compound A (3.51 g) was added to a 40 mL of dimethylformamide solution containing equal molar of benzaldehyde and 4 equivalents of triethylamine. The solution was refluxed at 60° C. for 16 hr and cooled at ice bath to produce a yellow precipitate. The precipitate was then collected and washed with ethyl acetate to give 3.3 g (83%) of the desired product 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-phenylmethylidenepiperazine-2,5-dione (Compound 1) as a mixture of isomers. The mixture was predominately the ZZ and EZ isomers.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH3:16])[CH3:3].Cl[C:18]1[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:11]=1)[CH2:5][N:4]([C:18]1[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(Br)cc1CNCC
Reactant: N#Cc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Temperature: 110 °C
Yield: 76.1 %

Procedure:
N-ethyl 2-propoxy-5-bromobenzylamine hydrochloride 2 (5.17 g, 16.8 mmol) and 3-chloro-6-cyanopyridazine (2.65 g, 16.8 mmol) were dissolved in NMP (25 ml) and sodium hydrogen carbonate added (3.54 g, 42.1 mmol). The mixture was heated at 110° C. under argon for 7.5 hours and then allowed to cool to ambient temperature. The mixture was poured into ethyl acetate (200 ml) washed with water (5×200 ml) and brine (200 ml), the organic phase dried over MgSO4 and concentrated in vacuo. The residue was purified by MPLC (20%ethyl acetate/hexane) and then crystallised from ether/hexane to give the title product (4.80 g, 76%).
Reaction SMILES: [OH-:1].[CH3:2][N+:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:5][C:4]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1.C[S:26]([OH:29])(=[O:28])=[O:27]>O1CCCC1>[S:26]([O-:29])([O-:1])(=[O:28])=[O:27].[CH3:2][N+:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:5][C:4]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1.[CH3:2][N+:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:5][C:4]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: CS(=O)(=O)O
Reactant: [OH-]
Agent: COC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)[n+](C)c1
Solvent: C1CCOC1
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 400 mg of 1-methyl-2-veratrylamino-5-methoxycarbonylpyrimidinium hydroxide dissolved in 15 ml of anhydrous tetrahydrofuran, are added 85 μl (1.1 eq; 1.31 mmol) of methanesulfonic acid. The mixture is stirred under argon at room temperature for one hour. The precipitate is filtered, rinsed with tetrahydrofuran and ether and then dried (weight: 490 mg--yield: 96%).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:18][C:19]1([CH3:45])[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[C:21](=[CH:22][C:23]([O:41][CH2:42][CH2:43][CH3:44])=[C:24](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=O)[CH:25]=2)[O:20]1>>[CH3:18][C:19]1([CH3:45])[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[C:21](=[CH:22][C:23]([O:41][CH2:42][CH2:43][CH3:44])=[C:24](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=2)[O:20]1
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(c1ccccc1)=CC(C)(C)O2
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (237 mg, 0.83 mmol) and (2E)-3-(2,2-dimethyl-4-phenyl-7-propoxy-2H-chromen-6-yl)-2-fluoro-but-2-enal (Compound 102, 107 mg, 0.29 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([O:23]C)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[OH2:23].[ClH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(Nc2ccnc3c(OC)cccc23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(Nc2ccnc3c(O)cccc23)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
In a flame dried single-neck round bottom flask equipped with a Dean-Stark trap and a condenser, a solution of 1.0 g (2.9 mmol) of N-(4-butylphenyl)-8-methoxyquinolin-4-amine hydrochloride and 20 mL of toluene was treated with 1.9 g (14.5 mmol) of anhydrous aluminum chloride. This was heated under reflux for five hours, and then allowed to cool to room temperature. The reaction solution was treated dropwise with water until a sticky solid formed. Work-up of the mixture eventually afforded mg of crude product. This was recrystallized from water-formic acid to furnish 340 mg (34%) of the title compound: m.p. 269° C.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:27]([F:30])([F:29])[F:28])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][O:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:26])[O:11]2)=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][CH2:9][C@:10]2([C:27]([F:29])([F:28])[F:30])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][O:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:26])[O:11]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(N3CCOC3=O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCO
Solvent: CCCCCC
Product: O=C1Nc2ccc(N3CCOC3=O)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
4-Fluoro-N-{[2-oxo-6-(2-oxo-1,3-oxazolidin-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:ethanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCc3ccccc3)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Then, 0.85 g of 2,6-dichloro-4-benzyloxyphenol, 0.48 g of potassium carbonate, 0.75 g of 2,3-dichloro-5-trifluoromethylpyridine and 10 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred at 85° to 90° C. for 3 hours. Then, the reaction solution was cooled to room temperature, poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 1.39 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-benzyloxybenzene, (yield, 98%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCCN=C=NCC.ON1[C:32]2[CH:33]=[CH:34][CH:35]=C[C:31]=2[N:30]=[N:29]1.NN1CCCCC1>C(Cl)Cl>[N:30]1([NH:29][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH:9]=2)=[O:15])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: NN1CCCCC1
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1cnc(-c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (150 mg, 075 mmol) in DCM (10 mL) is added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (158 mg, 0.83 mmol) and N-hydroxybenzotriazole (112 mg, 0.83 mmol) at rt and the mixture is stirred for 10 min. 1-Aminopiperidine (150 mg, 1.5 mmol) is added. The mixture is stirred at rt overnight. The mixture is washed with 2 N aqueous HCl (5 mL), saturated aqueous NaHCO3, (5 mL), and water (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid piperidin-1-ylamide (125 mg) as a solid. MS: 290 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:13])([C:9]([F:12])([F:11])[F:10])[CH2:5][C:4](=[O:14])[CH:3]=1.[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:13])([C:9]([F:10])([F:11])[F:12])[CH2:5][C:4]2([O:17][CH2:16][CH2:15][O:14]2)[CH:3]=1
Reactant: OCCO
Reactant: CC1=CC(=O)CC(C)(C(F)(F)F)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CC2(CC(C)(C(F)(F)F)C1=O)OCCO2
Temperature: 25 °C
Yield: 90.6 %

Procedure:
2.64 g (12.8 mmole) of 3,5-dimethyl-5-trifluoromethyl-2-cyclohexen- 1,4-dione(A-5) prepared in Example 6 and 1.59 g (25.6 mmole) ethylene glycol were mixed with 250 ml of toluene, and 0.1 g of p-toluenesulfonic acid was added as catalyst. After cooling to room temperature, the reaction mixture was washed with water and aqueous solution of sodium bicarbonate. The organic layer thus formed was dried using anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was fractionated with column chromatography using n-hexane/ethyl acetate(5:1, v/v) as eluent to produce the title compound(yield: 90.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1cccnc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3cccnc3)cn2n1

Procedure:
The title compound, white solid, MS: m/e=277.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 3-ethynylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)[CH2:15]3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(OCC2CCCCN(CC3(c4ccc(Cl)cc4)CCC3)C2)cc1
Yield: 39.8 %

Procedure:
To a stirring 0° C. solution of [1-(4-Chloro-phenyl)-cyclobutyl]-[3-(4-trifluoromethyl-phenoxymethyl)-azepan-1-yl]-methanone (0.13 g, 0.28 mmol) under N2 in toluene (2.8 mL, 0.1M) was added sodium bis(2-methoxyethoxy)aluminum hydride (65+weight % in toluene) (0.30 mL, 0.98 mmol) dropwise with stirring. When the reaction was complete by HPLC, the reaction was quenched with H2O. 10% NaOH and ethyl acetate were added, and the organic was removed, dried with Na2SO4, and concentrated. The crude reaction mixture was purified by silica gel chromatography (90:8:2 Hexanes:methylene chloride: 2N NH3 in ethyl alcohol). A 40% yield (0.0504 g) of pure material was obtained as well as other impure fractions. 1H NMR (CDCl3, 300 MHz) 7.54 (2H, d, J=8.9 Hz), 7.22 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.3 Hz), 6.87 (2H, d, J=8.8 Hz), 3.62-3.45 (2H, m), 2.89 (1H, d, J=13.7 Hz), 2.80 (1H, d, J=13.7 Hz), 2.60 (1H, td, J=13.3, 3.7 Hz), 2.55-2.36 (3H, m), 2.30-2.10 (4H, m), 2.08-1.90 (2H, m), 1.90-1.25 (7H, m) ppm. 13C NMR (CDCl3, 75 MHz) 161.75, 148.53, 130.96, 128.00, 127.91, 127.03, 126.98, 122.98, 114.61, 71.38, 70.53, 60.37, 58.87, 48.07, 39.52, 31.84, 31.64, 30.23, 29.50, 24.97, 16.24 ppm. LRMS: 451.53.
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C([O-])(=O)C.[Na+].C(O)C>O>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C(=O)N(c2ccc(Cl)c(Cl)c2)N=C1C

Procedure:
The starting material is prepared as follows: The mixture of 1.3 g of diethyl α-acetyl-malonate, 1.3 g of 3,4-dichlorophenylhydrazine hydrochloride, 0.5 g of sodium acetate, 30 ml of ethanol and 10 ml of water is warmed on the steam cone for 10 minutes. It is diluted with water, extracted with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in 50 ml of xylene, the solution distilled for 10 minutes and refluxed for 85 minutes. It is evaporated and the residue triturated with diethyl ether to yield the 1-(3,4-dichlorophenyl)-3-methyl-4-carbethoxy-2-pyrazolin-5-one, melting at 147°-148°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 5-phenyl-1-pentanol (3.28 g, 20 mmoles) and triethylamine (6.13 ml, 44 mmoles) in CH2Cl2 (35 ml) under N2, p-toluen-sulphonyl chloride (4.19 g, 22 mmoles) was added and then put under stirring up to room temperature for 1 night. The mixture was washed with water, NaHCO3 and 5% HCl, anhydrified and brought to dryness to give 6.55 g of the title compound (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@@H:10]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Na]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:11](=[O:26])[C@@H:10]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: [Na]
Solvent: ClCCCl
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate (0.050 g, 0.099 mmol, Example 21, Step C) and morpholine (0.013 mL, 0.149 mmol) in DCE (1.0 mL) was added sodium triacetoxyhydroborate (0.063 g, 0.297 mmol) at 0° C. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM) and the combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under the reduced pressure. This was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].Br[C:12]1C=CC=C(Br)C=1C.CN(C=O)C.[Cu]C#N>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Cc1c(Br)cccc1Br
Agent: N#C[Cu]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1C#N
Yield: 35 %

Procedure:
This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile. Data for 3-bromo-2-methylbenzonitrile: 1H NMR (400 MHz, acetone-d6) 7.88 (d, J=8.0, 1H), 7.73 (d, J=8.0, 1H), 7.32 (t, J=15.8, 7.9, 1H), 2.58 (s, 3H).