Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:21]([S:23][CH3:24])[NH:22][C:16]=2[C:15]1=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:27][C:28]#[C:29][CH3:30].[Cl-].[Na+]>CN(C)C=O>[CH2:7]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:21]([S:23][CH3:24])[N:22]([CH2:27][C:28]#[C:29][CH3:30])[C:16]=2[C:15]1=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nc2ccn(Cc3ccccc3)c(=O)c2[nH]1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(SC)nc2ccn(Cc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
2.07 g (15.0 mmol) of potassium carbonate were added to a solution of 4.0 g (14.7 mmol) of 5-benzyl-2-methylsulphanyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one and 1.31 ml (15.0 mmol) of 1-bromo-2-butyne in 100 ml of dimethylformamide and stirred for one hour at ambient temperature. Then approx. 200 ml of saturated sodium chloride solution were added and the mixture was extracted three times with 50 ml of ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:dichloromethane with 0–2% ethanol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 13.6 g (100.0 mmol) of 4-hydroxyacetophenone in 100 mL of DMF was added 20 g (144 mmol) of K2CO3, then 12 mL (101 mmol) of benzyl bromide. The reaction was stirred for 1.5 h at ambient temperature, then poured into 300 mL of H2O to give a white precipitate. This was filtered and washed with 50 mL of H2O. The product was taken up in 100 mL of CH2Cl2, and the H2O that separated was drained. The organic layer was extracted with H2O (1×25 mL) and brine (1×25 mL), dried over MgSO4, filtered, and concentrated to 22.1 g (98%) of a white solid as the titled compound. MS (ESI) m/e 226.9, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.50 (m, 3H) 5.21 (s, 2H) 7.11 (m, 2H) 7.41 (m, 5H) 7.92 (m, 2H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:24])[CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19])[CH3:14].N1C=CC=CC=1>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:18]([CH3:19])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:21]=1[CH3:22])=[O:24])[CH3:14]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C

Procedure:
Similar to Example 1, m-nitrophenylhydrazine hydrochloride (10 mmol, 1.9 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a 50% solution of pyridine in ethanol. A precipitate was formed in the reaction medium, and was collected by filtration. Analysis confirmed synthesis of the named product, m.p., 107.7° C.–109.2° C.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[CH:19]([C:21](=[O:24])[CH2:22][CH3:23])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:1][C:2]1[N:10]([CH:19]([C:21](=[O:24])[CH2:22][CH3:23])[CH3:20])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 25 °C
Yield: 7 %

Procedure:
The solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.0 g, 4.31 mmol), 2-bromopentan-3-one (1.1 g, 6.46 mmol), Cs2CO3 (2.8 g, 8.61 mmol), KI (142.9 mg, 0.86 mmol) in CH3CN (4 ml) were stirred at 70° C. for 2 h. After the reaction completed, the solution was cooled to r.t. and filtered off. The filtration was evaporated under vacuum. The residue was purified by flash column (Eluent: PE:EtOAc=5:1) to get tert-butyl 2-methyl-1-(3-oxopentan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (100 mg yield 7%)
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(O)c2oc(C)nc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)c2oc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To methyl 7-hydroxy-2-methyl-1,3-benzoxazole-5-carboxylate (400 mg, 2.07 mmol) in DMF (10 mL) was added ground potassium carbonate (570 mg, 4.14 mmol) and methyl iodide (0.142 mL, 2.28 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with ethyl acetate and washed with water. Organic phase was dried over sodium sulfate, filtered and concentrated to yield 368 mg (73%) of methyl 7-methoxy-2-methyl-1,3-benzoxazole-5-carboxylate as an off white solid. LC/MS=222 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>C(OCC)C>[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CCN(C)C1=O
Temperature: 40 °C
Reaction time: 21 h

Procedure:
13.20 g of 60% NaH (in paraffin oil) (0.33 mol) was added to 100 ml of dry diethyl ether. With vigorous stirring, 19.83 g (0.20 mol) of N-methylpyrrolidone were added. Then within one hour 121.30 g (0.83 mol) of diethyl oxalate were added dropwise. After the addition the suspension was heated to 40° C. and stirred for 21 hours. The reaction mixture was then cooled in an ice bath, mixed with 66 ml 5M HCl and the resulting 2-phase mixture was filtered once. Then the two phases were separated, and the aqueous phase was extracted twice with 100 ml diethyl ether. The combined ethereal phases were dried over Na2SO4 and concentrated on a rotary evaporator to dryness. The oily residue was cooled to −80° C. and mixed with 200 ml diethyl ether. The resulting brown solid was filtered off and recrystallized from heptane. This gave 5.2 g product as white needles.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl>[CH2:32]([O:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[S:21]1(=[O:23])=[O:22])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNC(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
To a solution of 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (235 mg, 0.356 mmol) in methylene chloride (2 mL) is added triethylamine (0.1 mL) then benzoyl chloride (56 mg, 0.4 mmol) and the mixture is stirred at RT for 2 h. The solvent is removed under reduced pressure and 1 N HCl is added. The mixture is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (7:3) as eluent to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:3]1=[O:15].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:47][C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[CH2:55][NH2:56]>ClCCl>[Cl:47][C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[CH2:55][NH:56][C:7]([CH:5]1[CH2:6][N:2]([CH3:1])[C:3](=[O:15])[N:4]1[CH2:10][C:11]([F:14])([F:13])[F:12])=[O:9]
Reactant: CN1CC(C(=O)O)N(CC(F)(F)F)C1=O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1CC(C(=O)NCc2ccc(Cl)cc2Cl)N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
A mixture of 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylic acid (84 mg, 0.37 mmol), 1-hydroxybenzotriazole hydrate (68.0 mg, 0.444 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85 mg, 0.444 mmol) and N-ethyl morpholine (0.189 ml, 1.480 mmol) in dichloromethane (9 ml) was stirred at room temperature for 10 minutes. A solution of [1-(2,4-dichlorophenyl)methyl]amine (65.1 mg, 0.37 mmol) in dichloromethane (1 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (10 ml) and the solution was washed with saturated sodium hydrogen carbonate solution (10 ml), water (10 ml), citric acid solution (10 ml) and brine (10 ml), dried and evaporated. The residue was purified by mass-directed automated HPLC. The residue was triturated with ether and the resulting solid was collected and dried to give N-[(2,4-dichlorophenyl)methyl]-1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxamide (60 mg, 42%). LC/MS [M+H]+=384, retention time=2.64 minutes.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)=[O:5])[CH2:3][CH2:2]1.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)C1CC1
Yield: 73.9 %

Procedure:
A mixture of the 23.6% toluene solution of o-nitrophenyl cyclopropyl ketone obtained in Example 7 (232.3 g, 0.286 mole ketone) and 2.86 g of 5% Pd/C catalyst is placed under H2 at 32-56 psig in a Parr hydrogenator. The hydrogen uptake is monitored and when the reaction is complete, the reaction mixture is filtered and concentrated in vacuo to give the title product, 39.5 g, 86.3% pure by HPLC analysis (73.9% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[C:19](#[N:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH2:20][C:19]#[N:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CC#N
Reactant: COc1ccccc1COc1cccc(C=O)c1
Product: COc1ccccc1COc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(2-methoxybenzyloxy)benzaldehyde gave 3-(3-(2-methoxybenzyloxy)phenyl)-3-hydroxypropanenitrile as yellow oil. Yield (0.88 g, 47%): NMR (400 MHz, CDCl3) δ 7.42-7.46 (m, 1H), 7.27-7.31 (m, 2H), 6.90-7.06 (m, 5H), 5.12 (s, 2H), 5.01 (m, 1H), 3.87 (s, 3H), 2.76-2.82 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH:8]2[CH:4]1[CH2:5][NH:6][CH2:7]2.Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:7][CH:8]2[CH:4]([CH:3]2[N:2]([CH3:9])[CH3:1])[CH2:5]1
Reactant: CN(C)C1C2CNCC21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CN(C)C1C2CN(CCCCl)CC21
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of N,N-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (1.45 g), 1-bromo-3-chloropropane (4.05 mL) and cesium carbonate (11.20 g) in acetone was heated to reflux for 7 h, cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 35:1 (v/v) DCM/MeOH) to afford the title compound as yellow oil (0.93 g, 40.00%), HPLC: 80.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 203.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[O:12][CH3:13].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O.O>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1

Procedure:
A solution of 1,3-difluoro-2-methoxy-4-nitrobenzene (1 g, 5.29 mmol) and aniline (0.53 mL, 5.82 mmol) in DMSO (10 mL) was heated at 100° C. for 4 h. The reaction mixture was diluted with water and the product extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-50% Et2O in cyclohexane) to yield the title compound as an off white solid (1.05 g, 76%). 1H NMR 400 MHz δ (CDCl3): 8.82 (1H, br s), 7.96 (1H, dd, J=9.5, 5.3 Hz), 7.32-7.26 (2H, m), 7.12-7.07 (1H, m), 7.02-6.98 (2H, m), 6.74 (1H, t, J=9.5 Hz), 3.53 (3H, d, J=1.1 Hz).
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[C:3]([F:6])([CH3:5])[CH3:4].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][Br:14])[C:3]([F:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(C(F)C(C)(C)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(F)C(F)c1cccc(CBr)c1
Temperature: 25 °C

Procedure:
A solution of 1-(1,2-difluoro-2-methylpropyl)-3-methylbenzene (2.747 g, 14.91 mmol), N-bromosuccinimide (2.65 g, 14.9 mmol) and 2,2′-azobis(isobutyronitrile) (0.1 g) in carbon tetrachloride (30 ml) was heated under reflux for 1.5 hrs. After cooling the reaction solution to room temperature, white precipitate was collected by filtration and washed with hexane. The solvent of the recovered filtrate was evaporated under reduced pressure to give a crude product of 3-(1,2-difluoro-2-methylpropyl)benzyl bromide as a yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2N3C(CN(CC4CC4)C)=NN=C3CN=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1.C=[O:30]>C(O)=O>[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:28]=1
Reactant: CN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2)CC1CC1
Reactant: C=O
Solvent: O=CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 1, 8-chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated in formic acid with aqueous formaldehyde to give 5-chloro-2-[3-[[(cyclopropylmethyl)methylamino]methyl]-5-](dimethylamino)methyl]-4-H-1,2,4-triazol-4-yl]benzophenone. This product is identical to that given in Example 21.
Reaction SMILES: [Li]CCCC.[CH:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16].Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH2:21]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20][CH2:19][CH2:18][C:16]#[C:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]#[CH:6]
Reactant: C#CCCCCCCCC#C
Reactant: BrCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCCCCCCCC#CCCCCOC1CCCCO1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
n-BuLi (4.86 mL of 2.5 M in hexanes, 12.16 mmol) was added dropwise to a −78° C. solution of undec-1,10-diyne (2.0 g, 13.51 mmol) in dry tetrahydrofuran/HMPA (105 mL, 6:1) under an argon atmosphere. After 30 min, the reaction mixture was warmed to −10° C. over 2 h and maintained at this temperature for 20 min, then re-cooled to −75° C. To this was added a solution of 2-(4-bromobutoxy)-tetrahydropyran (2.4 g, 10.14 mmol) in dry THF (15 mL). The resulting mixture was warmed to room temperature over 3 h, maintained at this temperature for 12 h, then quenched with sat. aq. NH4Cl (25 mL). After 20 min, the mixture was extracted with ether (2×125 mL). The combined ethereal extracts were washed with water (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 5% EtOAc/hexanes as eluent to give 2-(pentadeca-5,14-diynyloxy)tetrahydropyran (1.97 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.58 (t, J=2.5 Hz, 1H), 3.82-3.89 (m, 1H), 3.71-3.78 (m, 1H), 3.43-3.53 (m, 1H), 3.36-3.47 (m, 1H), 2.01-2.20 (m, 6H), 1.93 (t, J=2.5 Hz, 1H), 1.27-1.81 (m, 20H). Lit. ref: F. Slowinski; C. Aubert; M. Malacria Eur. J. Org. Chem. 2001: 3491.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(CCN2CCOCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=613.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 4-(chloroethyl)morpholine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][CH:13]([CH2:16][CH3:17])[CH:14]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:12][CH:13]([CH3:14])[CH2:16][CH3:17])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CCC(C)C=O
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCC(C)CNc1ccc(Cl)cc1C(=O)O

Procedure:
5-chloro-2-(2-methyl-butylamino)-benzoic acid was prepared from 2-amino-5-chloro-benzoic acid (23.31 mmol, 4.0 g) and 2-methylbutyraldehyde (23.31 mmol, 2.0 g) with sodium triacetoxyborohydride (96.62 mmol, 9.88 g) as per Procedure G (5.0 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][CH2:36][N:37]2[C:38](=[O:47])[C:39]3[C:40](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:42])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCN4C(=O)c5ccccc5C4=O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and N-(2-hydroxyethyl)-phthalimide were processed as described in Example 62A to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C2C(=CC=CC=2)N=C(CCl)[N:27]=1.C(OC1C=CC(NC)=CC=1)(C)C>Cl>[NH2:27][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: ClCc1nc(Cl)c2ccccc2n1
Reactant: CC(C)Oc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: CNc1ccc(OC(C)C)cc1
Agent: Cl
Product: CC(C)Oc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: The title compound was prepared from 4-chloro-2-chloromethyl-quinazoline (300 mg, 1.4 mmol), 4-isopropoxy-N-methylaniline (279 mg, 1.7 mmol) and concd HCl (12 M, 10 drops) by a procedure similar to Example 203c with subsequent MPLC purification. 1H NMR (CDCl3) δ 7.8 (d, 1H), 7.55 (m, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.7 (s, 2H), 4.5 (sept, 1H), 3.6 (s, 3H), 1.37 (d, 6H); LC-MS (ESI+; 342 ([M+H]+)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](CCO)[CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[C:15]([CH3:21])[N:14]=3)[N:12]=2)=[C:4]([F:25])[CH:3]=1.C(NN=C(N)C)(C)C.CN(C([O:41]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([N:14]=[C:15]([NH:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH3:21])=[O:41])[N:12]=2)=[C:4]([F:25])[CH:3]=1
Reactant: Cc1nc(-c2cn(CCO)c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CC(N)=NNC(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1c[nH]c(-c2ccc(Br)cc2F)n1)NNC(C)C

Procedure:
Reaction of 30 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 31 which cyclizes upon heating to give V.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]=[CH2:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])C=C>>[Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]/[CH:16]=[CH:17]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C=CCc1ccccc1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)/C=C/Cc1ccccc1O[Si](C)(C)C(C)(C)C
Yield: 90.7 %

Procedure:
The representative procedure was followed using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil (158 mg, 91%).