Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.CCCCCC.C([Li])CCC.[Cl:27][Si:28](Cl)([Cl:30])[Cl:29]>C(OCC)C>[Cl:27][Si:28]([Cl:30])([Cl:29])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (175 mL) of 1-bromo-3,5-di-tert-butylbenzene (35.00 g, 130.00 mmol), a 1.65 M hexane solution of n-butyllithium (88.67 mL, 143.00 mmol) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 2 hours. The resultant mixture was added dropwise to a solution of tetrachlorosilane (66.26 g, 390.00 mmol) dissolved in diethyl ether (58 mL) at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure. Purification by distillation under reduced pressure afforded trichloro(3,5-di-tert-butylphenyl)silane (24.11 g, yield 57.3%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19]C(=O)C)[CH2:14][CH2:13]1.[BrH:23]>O>[BrH:23].[BrH:23].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][NH2:19])[CH2:16][CH2:17]1
Reactant: CC(=O)NCC1CCN(CC2COc3ccccc3O2)CC1
Agent: Br
Solvent: O
Product: NCC1CCN(CC2COc3ccccc3O2)CC1
Reaction time: 4 h

Procedure:
A mixture of 2 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]acetamide, 15 parts of a hydrobromic acid solution 48% in water and 10 parts of water was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated. The residue was crystallized from a mixture of ethanol and acetonitrile. The product was filtered off and dried, yielding 2 parts of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinemethanamine dihydrobromide; mp. 235.3° C. (intermediate 90).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: CC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 59.4 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.140 g, 0.53 mmol) was reacted with 1-(4-aminophenyl)propan-2-one (0.094 g, 0.63 mmol) to afford the title compound (0.119 g, 60%) as a light yellow solid. MW=377.87. 1H NMR (DMSO-d6, 500 MHz) δ 8.84 (s, 1H), 8.29-8.22 (m, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.55-7.48 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 3.74 (s, 2H), 2.94-2.84 (m, 4H), 2.15 (s, 3H), 2.14-2.06 (m, 2H); APCI MS m/z 378 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23](Br)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(O)CC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(Br)cccc3[nH]2)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc23)cn1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
An argon stream is bubbled through a solution of 182 from above (500 mg, 1.2 mmol) and 2-methoxy-5-pyridine boronic acid (181 mg, 1.2 mmol) in 4 ml of 1-propanol for 15 min. Then 2M aqueous sodium carbonate solution (1.2 ml, 2.4 mmol) and bis(triphenylphosphine)palladium-(II)-chloride (50 mg, 0.07 mmol) are added and the reaction mixture is stirred at 85° C. for 3 h. Then the mixture is cooled to 0° C. and ethyl acetate and concentrated sodium hydroxide solution is added until a pH of 11 is reached. The solution is washed with brine and the organic layers are dried over sodium sulfate and evaporated. The crude product is purified by flash-chromatography (silica gel, cyclohexane/ethyl acetate 7:3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:14][C:13]=1[C:26]#[N:27].Cl.O1CCOCC1>>[NH2:27][C:26]1[C:13]2[N:14]=[C:15]([CH2:22][CH2:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[C:12]=2[C:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=2[N:1]=1
Reactant: CCCCc1nc(C#N)c(-c2ccc(C(=O)OC)cc2N)n1CC(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 32 %

Procedure:
To 5-(2-amino-4-methoxycarbonylphenyl)-2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile S6 (118 mg, ˜90% pure, 0.27 mmol, 1.0 equiv) was added 4 N HCl in dioxane (2.0 mL, 8.0 mmol, 30 equiv) at 25° C. The reaction was heated at reflux for 15 h then cooled to 25° C. The reaction was concentrated in vacuo and partitioned between 1:9 MeOH/EtOAc (50 mL) and saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with 1:9 MeOH/EtOAc (3×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Purification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient) afforded the title compound 420 (95 mg, 32% over 2 steps) as an off white solid: 1H NMR (CD3OD, 600 Hz) δ1.02 (t, J=6.6 Hz, 3H), 1.28 (br s, 6H), 1.51 (hex, J=7.8 Hz, 2H), 1.88 (pent, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 3.95 (s, 3H), 7.86 (dd, J=8.4, 1.8 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H); 13C NMR (CD3OD, 150 Hz) δ 12.8, 22.2, 27.2, 29.7, 48.1, 51.3, 54.8, 71.1, 117.9, 118.6, 121.0, 121.3, 127.2, 127.9, 134.0, 143.6, 152.1, 157.3, 167.2; MS (APCI+): calcd C20H27N4O3 [M+H]+ 371.5. found 371.5.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1.[C-:25]#[N:26].[Na+]>CN(C)C=O.O>[C:25]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)#[N:26]
Reactant: [C-]#N
Reactant: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(C#N)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
To 140 mg 6-bromo-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)4,5-dihydro-4-methyl-5-oxo-imidazo(1,5-a)quinazoline in 5 ml dimethyl formamide (DMF) 40 mg cuprous cyanide was added. Thereafter further 5 ml DMF was added and the resulting mixture was heated to 130°-150° C. for 60 minutes with stirring. To this mixture 110 mg sodium cyanide in 5 ml water was added and thereafter further 30 ml water. The resulting mixture was extracted with 30 ml ethyl acetate and thereafter four times with 20 ml ethyl acetate. The combined organic phase was washed with water and dried with calcium chloride. Evaporation in vacuo gave 24 mg of the title compound. M.p. 115°-125° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].CC1C=CC=CC=1.[F:22][C:23]([F:28])([F:27])[CH:24]([OH:26])[CH3:25].[H-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([O:26][CH:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])(=[O:12])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(OS(=O)(=O)c1ccc2ccccc2c1)C(F)(F)F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a cooled (ice-bath) suspension of 41.7 parts of 2-naphthalenesulfonyl chloride in 174 parts of methylbenzene were added dropwise 20.0 parts of 1,1,1-trifluoro-2-propanol. After stirring for 1 hour, there was added dropwise a mixture of 9.6 parts of a dispersion of sodium hydride in mineral oil (50%) and some methylbenzene while cooling on ice. Subsequently, the whole was diluted dropwise with water. The organic layer was separated, dried, filtered and evaporated, yielding 53.2 parts (99.9%) of (2,2,2-trifluoro-1-methylethyl) 2-naphthalenesulfonate (interm. 28).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Sc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(CSc2nc3ccccc3s2)cc1
Yield: 68.2 %

Procedure:
A solution of 28.1 g (0.2 mol) of benzyl chloride in 50 ml of ethanol is added slowly, with stirring, to a solution of 33.4 g (0.2 mol) of 2-mercaptobenzothiazole and 8 g (0.2 mol) of NaOH in 150 ml of ethanol and 25 ml of water. The resulting solution is refluxed for 2.5 h. After cooling, it is filtered and evaporated to leave 35.1 g of a yellowish solid melting at 39°-40° C. 1H NMR (CDCl3): δ4.41 (2H), δ6.98-7.8 (9H) ppm.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][C:5]#[N:6].[CH3:7][CH2:8][OH:9]>C(OCC)C>[ClH:1].[CH2:8]([O:9][C:5](=[NH:6])[CH2:4][O:3][CH3:2])[CH3:7]
Reactant: COCC#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)COC
Temperature: -10 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Hydrochloric acid gas is bubbled through a solution of methoxyacetonitrile (26 g, 0.37 mol) in EtOH (22 mL) and diethyl ether (118 mL), which is chilled to −10° C. for twenty minutes. The reaction vessel is capped and stirred for 17 hours at ambient temperature. The mixture is cooled to −10° C. The solid that forms is collected by filtration, washed with diethyl ether and air dried to afford 2-methoxy-acetimidic acid ethyl ester hydrochloride (49.3 g, 87%) as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=O)C.C([O-])([O-])=O.[K+].[K+].O>CO>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2cc(COC(C)=O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a solution of 0.9 g (3.49 mmol) of methyl 6-acetoxymethyl-2-naphthoate in 100 mL of MeOH was added 0.5 g (3.62 mmol) of K2CO3 and 1 mL of H2O. The mixture was stirred at room temperature for 30 min before being evaporated to dryness. The residue was taken up in 50 mL of EtOAc and 30 mL of H2O. The organic layer was dried (Na2SO4) and evaporated to give 0.76 g (100% yield) of methyl 6-hydroxymethyl-2-naphthoate as white crystals: mp 123°-124° C.; IR (mull) 3250, 1720, 1300, 1200, 1130, 1100, 1040, 1020, 920, 900, 840, 820, 760 cm-1 ; 1H NMR (CDCl3) δ2.13 (s, 1, OH), 3.98 (s, 3, CO2CH3), 4.88 (s, 2, CH2OH), 7.3-8.7 (m, 6, ArH); MS calcd for C13H12O3 216.0786, found 216.0787.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.[CH3:23]S(C)=O>>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@@H:11]2[CH2:23][C@H:12]2[C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:19])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CS(C)=O
Reactant: CC(C)N1CCN(C(=O)/C=C/c2cnn(C)c2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2cnn(C)c2)CC1
Temperature: 50 °C
Yield: 9 %

Procedure:
45A (380 mg, 1.45 mmol) dissolved in 5 mL of anhydrous DMSO was added to a suspension containing (CH3)3S(I)O (3188 mg, 14.48 mmol) prereacted with NaH (579 mg, 14.48 mmol) in 15 mL of anhydrous DMSO. The reaction mixture was heated at 50° C. in an oil bath overnight. The reaction mixture was concentrated under high vacuum to remove as much DMSO as possible, the resulting crude material was then dissolved in EtOAc and washed with a small amount of H2O. The aq. phase was extracted with EtOAc (2×50 ml). The organic phases were combined dried over MgSO4 then filtered on a thin pad of silica gel (1 cm). The silica gel was washed with more EtOAc and the resulting solution was concentrated under reduced pressure then purified on a 40 g silica column on the Companion machine using 0 to 20% MeOH in EtOAc gradient (with two 10 plateau at 10% MeOH then at 20% MeOH). The desired fractions were combined and concentrated under reduced pressure. These fractions were found to still contain some starting material. These samples were combined and repurified on preparative reverse phase chromatography (LCMS) using the long high pH 35-55% gradient on the XBridge Prep C18 OBD, 30×150, 5 um column. The pure fractions were combined and concentrated under reduced pressure. The resulting residue was placed under high vacuum overnight. The yellow liquid was dissolved in 1 ml of distilled H2O and 300 μL of HCl 2N was added to the solution which was then filtered and freeze dried to yield 46.4 mg 45B (9% yield) as a yellow solid HCl salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.46-1.60 (m, 1H) 2.28-2.48 (m, 2H) 2.99-3.30 (m, 4H) 3.52-3.64 (m, 3H) 4.04 (s, 3H) 4.54-4.78 (m, 2H) 8.01 (s, 1H) 8.03 (s, 1H). ES[M+H]+=277.2, HRMS[M+H]+ calc. for C15H24N4O+H=277.20229, [M+H]+ obs.=277.20211.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].Cl>C(N(CC)CC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccccc1Br
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1Cl
Temperature: 25 °C
Yield: 99.3 %

Procedure:
2-Bromochlorobenzene (54.1 ml, 0.46 mol) and trimethylsilylacetylene (72 ml, 0.51 mol) were dissolved in triethylamine (250 ml). Triphenylphosphine (0.4 g, 1.5 mmol), copper (I) iodide (0.3 g, 1.6 mmol) and bistriphenyphosphinepalladium (II) dichloride (0.5 g, 0.67 mmol) were added and the mixture was heated under reflux for 18 h. The reaction mixture was cooled to ambient temperature and carefully added to 10% hydrochloric acid (480 ml). The product was extracted into hexane (3×200 ml), the extracts were washed with 10% hydrochloric acid (200 ml) and water (2×200 ml) then dried (MgSO4) and evaporated in vacuo to give (2-chlorophenylethynyl)-trimethylsilane (95.4 g) as an orange oil, which was used without further purification.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1C
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
To a solution of ethyl (3R*,4R*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate (2.75 g, 10.0 mmol) in dichloromethane (30 mL), benzyl chloroformate (2.14 mL, 15.0 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. Benzyl chloroformate (2.14 mL, 15.0 mmol) was also added to the mixture, and the mixture was stirred at room temperature for another 14 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1→4:1→4 2:1) to obtain 1.64 g of the title compound (5.37 mmol, 2 steps, 54%) as a colorless transparent oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cn1c(=O)cc(CBr)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(CN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Yield: 64.6 %

Procedure:
A suspension of 4-bromomethyl-l-methyl-2(1H)-quinolinone (756 mg, 3 mmol), 3-(4-piperidinyl)-1H-indole (600 mg, 3 mmol) and sodium hydrogencarbonate (378 mg, 4.5 mmol) in dry dimethylformamide (5 ml) was allowed to react at 80 ° C. for 2 hours. The reaction mixture was poured into water and the separated solid was filtered off. The solid was washed with water, dried and then recrystallized from methanol/tetrahydrofuran to give the desired product (III16) (720 mg, yield 65%). Mp 228°-229 ° C. (methanol/tetrahydrofuran).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[Cl:19])[CH:3]=2)=[O:18])=[CH:12][N:13]=1
Reactant: Nc1cc(NC(=O)c2ccc(Cl)nc2)ccc1Cl
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2Cl)c1)c1ccc(Cl)nc1

Procedure:
N-(3-amino-4-chlorophenyl)-6-chloronicotinamide (0.2 mmol) was used in general procedure 2 with 2-chlorobenzoic acid (0.8 mmol). The product was purified by RP-HPLC to give 6-chloro-N-(4-chloro-3-(2-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 419.8 (M)+
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=O)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:52][O:53][NH3+:54]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:54][O:53][CH3:52])[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CO[NH3+]
Reactant: CC(C)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C#CC1CC(CC(C)C)C1)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-(3-isobutylcyclobutyl)-4-oxo-5-hexynoate (58.1 g) and methanol (300 mL) were mixed. To the mixture were added sodium sulfate (21.55 g), pyridine (30 mL) and O-methylhydroxylammonium chloride (12.67 g) at ice temperature. The mixture was stirred at RT overnight and the resultant precipitate was removed by filtration. After concentration of the filtrate in vacuo, toluene (350 mL) was poured into the residue. The mixture was washed with 1 N hydrochloric acid (300 mL), water (300 mL) and brine (150 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (80 g) and ethyl acetate/hexane=1/20 (600 mL) to the residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (55.54 g) as a crude product.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([OH:11])/[CH:8]=[CH:9]/[I:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([C:18](Br)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([O:11][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)/[CH:8]=[CH:9]/[I:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC(/C=C/I)CC1CCCC1
Solvent: c1ccncc1
Product: I/C=C/C(CC1CCCC1)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 21.4 g. of 4-cyclopentyl-1-iodo-trans-buten-3-ol (Example 34) in 170 ml. of dry pyridine containing 31 g. of triphenylmethyl bromide is heated on the steam bath for 2 hours. The dark mixture is poured into 850 ml. of iced water and the resulting solution is extracted three times with ether. The combind extracts are washed with ice cold 2% hydrochloric acid until the washings are acidic, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Trituration of the residue followed by filtration removes triphenylcarbinol. The mother liquor is taken to dryness and the residual syrup is chromatographed on 400 g. of florisil using hexane gives 32 g. (78%) of syrup which solidifies on standing. Recrystallization from hexane affors white crystals, m.p. 87°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:12]1[CH2:17][CH2:16][CH:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:14][CH2:13]1
Reactant: OC1CCOCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 4-hydroxybenzoate (30 g, 197 mmol, 1.0 mole equivalents), tetrahydro-4-pyranol (24 ml, 251 mmol, 1.3 mole equivalents) and triphenylphosphine (78 g, 297 mmol, 1.5 mole equivalents) in tetrahydrofuran (600 ml) at room temperature, was added diisopropyl azodicarboxylate (58 ml, 298 mmol, 1.5 mole equivalents) over a period of 15 minutes. The reaction mixture was stirred for 24 hours at room temperature. Another portion of diisopropyl azodicarboxylate (5 ml) and tetrahydro-4-pyranol (2 ml) was added and the reaction mixture was stirred for another 2 hours at room temperature. The reaction mixture was then quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate (500 ml) and ethyl acetate (500 ml). The organic phase was washed with water (2×250 ml), dried (magnesium sulfate), and was then concentrated in vacuo to give the crude product, methyl 4-(tetrahydro-2H-pyran-4-yloxy)benzoate, as a thick yellow oil (182 g).