Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:20]#[N:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3([C:20]#[N:21])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:13]=2)=[N:6][C:7]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2ccc(-c3cnc(N)cn3)cc2)CCOCC1
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(-c3cnc(N)c(Br)n3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(5-aminopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile (1.08 m, 3.84 mmol) in DMF (30 mL) was added N-bromosuccinimide (747 mg, 4.22 mmol) in one portion. The reaction was then stirred at room temperature for 1 h. At completion, the mixture was poured over ice (50 mL) and stirred for 20 min. After filtration and washing with water and drying under vacuum, 4-(4-(5-amino-6-bromopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile was obtained as obtained as a dark brown solid (1.37 g, 100% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), tert-butyl 2-aminoacetate (18.66 mg, 0.142 mmol), and TEA (0.033 mL, 0.237 mmol) in DMF (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=451.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.9 Hz, 0.4H), 1.45 (s, 9H), 1.47 (d, J=6.5 Hz, 2.6H), 1.71-1.83 (m, 1H), 2.02-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.55 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.06-3.21 (m, 4H), 3.37-3.47 (m, 1H), 3.50-3.63 (m, 1H), 3.72-3.84 (m, 1H), 6.63 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:9])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([NH:3][C:4]1[O:9][C:8]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)=[N:7][N:6]=1)[CH3:2]
Reactant: CCNC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCNc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)o1

Procedure:
The compound is prepared by a method analogous to that of Example 40 from N-ethyl-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2-hydrazine dicarboxamide and phosphorus oxychloride. The analytical values are summarized in Table III.
Reaction SMILES: [CH2:1]([C:5]1[NH:21][C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][CH:25]([N:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=2)=[N:30][N:29]=[N:28]1)[CH3:26])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:21]([CH2:44][C:41]2[CH:40]=[CH:39][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[N:27]([CH:25]([O:24][CH2:22][CH3:23])[CH3:26])[N:28]=[N:29][N:30]=3)=[CH:43][CH:42]=2)[C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2[nH]1
Reactant: CCOC(C)n1nnnc1-c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.7 %

Procedure:
2.1 g(0.0075 mole) of the compound obtained in step 9 and 3.6 g(0.009 mole) of 2'-[1-(1-ethoxyethyl)-1H-tetrazol-5-yl]-biphenyl-4-ylmethyl bromide were dissolved in 20 ml of dimethyl formamide and to the resulting solution was added 2.1 g(0.015 mole) of K2CO3. The resultant was stirred for 5 hours at room temperature and diluted with 100 ml of ethyl acetate, and washed with water(50 ml×3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified with column chromatography(5% MeOH/CH2Cl2) to obtain 2.85 g of the title compound(yield 65%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:16]([N:15]1[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=[C:6]1[CH:2]([NH:1][CH2:28][CH:27]([O:30][CH3:31])[O:26][CH3:25])[CH:3]([CH3:5])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Temperature: 135 °C
Yield: 58.6 %

Procedure:
To a solution of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.87 g, 5.48 mmol) in DMF (30 mL) was added bromoacetaldehyde dimethylacetal (2.78 g, 16.44 mmol) and potassium carbonate (2.27 g, 16.44 mmol) and the resulting suspension was heated at 135° C. for 18 h. The cooled reaction was concentrated in vacuo, triturated with methylene chloride to remove any solids, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 2:1 hexanes:ethyl acetate) to give the title compound as a pale yellow oil (1.38 g, 59%). MS(ES+) m/e 430 [M+H]+.
Reaction SMILES: C([N:8]1[C@@H:13]([CH:14]=[CH:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH:14]=[CH:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)C=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(1-isopentenyl)piperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(1-isopentenyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 157.5-156.5° C.; 1H NMR (250 MHz) δ9.37 (br. d, 2H), 5.59-5.46 (m, 2H), 4.19 (s, 1H), 3.59 (s, 1H), 2.66-2.59 (m, 1H), 1.8-1.5 (m, 9H), 1.0 (pair of d, 6H); 13C NMR (62.7 MHz) δ143.6 (s), 120.6 (s), 48.3 (s), 47.9 (s), 28.9 (s), 28.6 (s), 27.3 (s), 23.01 (s), 22.6 (s), 17.5 (s), 16.9 (s). FT-IR (neat): 3426, 3188, 3018, 2952, 1625, 1584, 1464, 1359, 1180, 1099, 958, 881. Elemental Analysis for C11H22NCl: C, 64.84%; H, 10.91%; N, 6.87%. Found: C, 64.06%; H, 10.77%; N, 6.78%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Br:14])[C:11](Cl)=[N:10][CH:9]=1.[CH2:17]([OH:20])[CH2:18][OH:19]>>[C:4]([O:3][CH2:4][CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Br:14])[C:11]([O:19][CH2:18][CH2:17][O:20][C:7](=[O:6])[CH3:8])=[N:10][CH:9]=1)(=[O:3])[CH3:5]
Reactant: OCCO
Reactant: O=C(OCCO)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOC(=O)c1cnc(OCCOC(C)=O)c(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.29 g, 60% purity in mineral oil) was dissolved in ethylene glycol (25 ml) and the raw material of step 1 was added. This mixture was stirred at 60° C. for 1 h. Volatiles were evaporated at 95° C., 1 mbar. The remainder was suspended in pyridine (25 ml), acetic anhydride (25 g) was added slowly during 30 minutes with stirring and stirring continued for 1 h. The mixture was partitioned between ethyl acetate and water, the organic phase was washed with 2N HCl and saturated sodium bicarbonate solution, dried over sodium chloride and evaporated to dryness in vacuo.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([NH:19]C(=O)OC(C)(C)C)[N:15]=[CH:16]2)=[CH:11][N:10]=1>ClC(Cl)C>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([NH2:19])[N:15]=[CH:16]2)=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2cnc(Cl)cc2cn1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2cnc(Cl)cc2cn1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Trifluoroacetic acid (0.43 mL, 5.5 mmol) was added to a solution of tert-butyl 7-chloro-2,6-naphthyridin-3-ylcarbamate (410 mg, 1.4 mmol) in dichloroethane (7 mL). After 4 hours, the reaction mixture was concentrated in vacuo, diluted with methylene chloride (50 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-100% ethyl acetate in heptane) to afford the title compound as a yellow solid (230 mg, 86%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C)C(=O)C>[N+:39]([C:36]1[CH:35]=[CH:34][C:33]([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]3=[CH:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(N)cc43)cc2)CC1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(NC(=O)Oc5ccc([N+](=O)[O-])cc5)cc43)cc2)CC1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
An amount of 200 mg (0.53 mmol) of (4Z)-6-amino-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione and 4-nitrophenyl chloroformate 320.0 mg (1.59 mmol) is stirred in N,N-dimethylacetamide at 100° C. for 1 hour. After cooling, the solvent is evaporated and stirred in 3 mL of water for 10 minutes. The solid precipitate is collected with ether to give 180 mg (70% yield) of (4-{[4(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dioxo-1,2,3,4-tetrahyro-isoquinolin-6-yl)-carbamic acid 4-nitro-phenyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1.CO.[H][H]>[OH-].[OH-].[Pd+2].C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]([NH2:13])=[CH:5][N:4]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cnc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(N)cnc1OC
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-Methoxy-3-carbomethoxy-5-nitropyridine (850 mg, 4 mmol) was added to a medium pressure Parr shaker bottle (250 mL) containing 100 mg of 20% Pearlman's catalyst (palladium hydroxide/carbon) and 50 mL of methanol. The bottle was pressurized to 50 psi of hydrogen and shaken for 2 hours. By TLC, no starting material was observed (98/2 CH2Cl2 /MeOH). The catalyst was filtered off, the methanol was removed under reduced pressure and the product used in the next step without further purification. Recovered 680 mg of product (95% yield).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH:13]([CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18]4)[C:14](=[O:15])[C:7]3=[CH:6][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH:13]([CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:19][CH2:18]4)[C:14](=[O:15])[C:7]3=[CH:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)cc1n2CC(CC2CCN(Cc3ccccc3)CC2)C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C1c2cc3cc(O)ccc3n2CC1CC1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
A solution of 2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one (1.599 g, 4.12 mmol) in 95 ml of methylene chloride was treated with potassium carbonate (5.696 g, 41.2 mmol) and cooled to -78° C. Boron tribromide (BBr3) was added dropwise to the cooled solution. After addition, the resulting solution was stirred at 0° C. for one hour, then at room temperature overnight. The mixture was treated with 36 g of potassium carbonate and 100 ml of water and stirred for one hour. The organic layer was separated, washed with water, dried and concentrated to give 1.652 g of yellow solid which was purified through silica gel column chromatography to give 0.988 g of the title compound. This material was recrystallized from ethyl acetate to give brown crystals, mp. 186°-188° C. Anal. Calc. for C24H26N2O2.0.1H2O: C, 76.60; H, 7.02; N, 7.45; Found C, 76.45; H, 7.18; N, 7.38.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:12]2[CH2:13][CH2:14][CH:9]([C:2]([OH:15])([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][CH2:11]2)=[CH:21][CH:22]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CC(O)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: CC(O)(c1ccccc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
The mixture of 2 g of α-methyl-α-(4-piperidyl)-benzyl alcohol, 1.95 g of 4'-fluoro-4-chlorobutyrophenone, 2 g of sodium carbonate (anhydrous), a crystal of sodium iodide and 150 ml of 4-methyl-2-pentanoneare stirred and refluxed for 72 hours. The reaction mixture is filtered to remove the inorganic salts and the filtrate evaporated under reduced pressure. Diethyl ether is added to the residue and the resulting solutionextracted with 5% aqueous hydrochloric acid. The aqueous solution is made basic with ammonia and extracted with diethyl ether. The extract is then dried and evaporated under reduced pressure to afford the 4'-fluoro-4-[4-(α-hydroxy-α-methylbenzyl)-piperidino]-butyrophenone of the formula ##SPC5##
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:27](O)[C@H:28]([C@H:30]([C@@H:32]([C@@H:34]([CH2:36][OH:37])[OH:35])[OH:33])[OH:31])[OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:27][CH:28]([OH:29])[CH:30]([OH:31])[CH:32]([OH:33])[CH:34]([OH:35])[CH2:36][OH:37])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)C(O)C(O)C(O)CO)cc1

Procedure:
In the manner described in Example 7, 3.62 g. of 4-(n-hexadecylamino)benzoic acid, 1.82 g. of mannitol, and 2.06 g. of p-toluene sulfonic acid are reacted to yield a mixture of mono- and bis-acylated products. Pure 2,3,4,5,6-pentahydroxyhexyl 4-(n-hexadecylamino)benzoate is separated from the mixture by adsorption chromatography using silica gel as the adsorbant.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:15]>Cl.O1CCCC1>[ClH:1].[C:8]([O:9][CH2:10][C:11]([NH2:12])([CH3:14])[CH3:13])(=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CC1(C)COC(c2ccccc2)=N1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To 8.7 g (0.041 mol) 2-phenyl-4,4-dimethyl-1,3-oxazoline hydrochloride suspended in 120 ml anhydrous hydrogen chloride in tetrahydrofuran (1M) was added 3.6 ml (0.20 mol) water. The mixture was warmed to cause solution and heated under reflux with stirring for 1 hour. The tetrahydrofuran was removed under reduced pressure to afford a nearly colorless oil which crystallized at 0° following the addition of anhydrous ether. The solid was triturated with anhydrous ether overnight and isolated by filtration under a nitrogen atmosphere. After drying in vacuo over calcium sulfate, 6.9 g (0.30 mol), 73%, 2-amino-2-methyl-1-propyl benzoate hydrochloride was obtained as a white solid, mp 225°-228° (dec.) acetone:hexane, ir (KBr) 1725 (c=o) cm-1, pmr (D2O) δ 1.50 (s, 6H), 4.4 (s, 2H) and 7.0-8.3 (m, 5H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH:7]([NH2:9])[CH3:8])[CH3:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1.[OH-].[K+]>O.ClCCCl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:10][CH3:11])=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCN(CC)CCCC(C)N
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: CCN(CC)CCCC(C)NC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture containing 970 g. (6.2 moles) of freshly distilled N1,N1 -diethyl-1,4-pentanediamine, 4 l. of 1,2-dichloroethane and 1 l. of water at 5°-10° C. there was simultaneously added dropwise a solution containing 5.95 moles of 4-chloro-2-nitrobenzoyl chloride in approximately 8 l. of 1,2-dichloroethane and a solution containing 410g. (6.2 moles) of 85% potassium hydroxide in 1 l. of water. When the addition was complete the ice bath was removed and stirring was continued 0.5 hours at room temperature. The organic layer was separated, dried over anhydrous calcium sulfate and evaporated to dryness under vacuum. The residue was dissolved in 3 l. or 1,2-dichloroethane and the resulting solution was treated with decolorizing carbon and filtered. The filtrate was diluted to 6 l. with additional 1,2-dichloroethane to give a pale yellow solution of 4-choro-N-[4-(diethylamino)-1-methylbutyl]-2-nitrobenzamide which was divided into three equal portions which were used directly in the next step.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[Na+].[I-].[Si]([C:17](F)([F:19])[F:18])(C)(C)C>C1COCC1>[F:18][C:17]1([F:19])[C:2]2([CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C=C1CC(C(=O)OCC)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(C1)CC2(F)F
Yield: 73.7 %

Procedure:
The solution of ethyl 3-methylenecyclobutanecarboxylate (1 g, 7.13 mmol), NaI (0.214 g, 1.427 mmol) and TMSCF3 (2.54 g, 17.83 mmol) in THF (10 mL) was stirred at 65° C. for 2 h. The reaction mixture was quenched with a 10% aq. solution of NaHCO3 and the aqueous layer was extracted with diethyl ether (3×10 mL). The combined organic layer was washed with a 10% aq. solution of NaHCO3, followed by brine, then dried over Na2SO4, filtered and the filtrate concentrated. The crude was purified by silica gel chromatography (12 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 320A as a pale yellow liquid (1 g, 73%, mixture of cis and trans isomers). 1H NMR (400 MHz, chloroform-d) δ ppm 4.13-4.24 (m, 2H) 2.56-2.65 (m, 1H), 2.01-2.06 (m, 2H), 1.91-1.98 (m, 2H) 1.16-1.45 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)O2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30]([NH2:33])[CH2:31][NH2:32].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:33][CH2:30][CH2:31][N:32]3[CH2:18]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)c2ccccc21
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: Clc1ccc(C2CN3CCN=C3c3ccccc32)cc1
Temperature: 200 °C
Yield: 70.1 %

Procedure:
A mixture of 60 g of 3-(4chlorophenyl)-3-methyl-1(3H)-isobenzofuranone and 257 g of ethylenediamine p-toluenesulfonate (166 ml ethylenediamine treated with 470 g p-toluenesulfonic acid and crystallised from 2-propanol) was heated to 200° C. and kept at this temperature overnight. The reaction mixture was allowed to cool and 850 ml of an aqueous 1N hydrochloride solution were added. The resulting mixture was extracted with 600 ml of chloroform. The organic layer was washed with 700 ml of an aqueous 1N potassium hydroxide solution, dried and evaporated in vacuo. The residue was crystallised from a 1:3 mixture of diethyl ether and hexane at -20° C. to give 46 g of (rac)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinoline as a yellow solid. The hydrochloride salt was prepared by the addition of a solution of hydrochloric acid in methanol resulting in (rac)6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinoline hydrochloride, melting point 230° C.