Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4S[C:30]([CH:33]5[CH2:38][NH:37][CH2:36][CH2:35][NH:34]5)=[CH:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].Br[C:43]1SC(C2CNCCN2)=C[CH:44]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][C:30]([CH:33]5[CH2:38][NH:37][CH2:36][CH2:35][NH:34]5)=[CH:44][CH:43]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: Brc1ccc(C2CNCCN2)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C5CNCCN5)s4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C5CNCCN5)cc4)cc23)CC1
Yield: 25.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-(4-bromophenyl)piperazine (94 mg, 0.39 mmol) for 2-(5-bromo-2-thienyl)piperazine to afford 20.5 mg of the title compound (25.9%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[CH:5]=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH2:16][C:17]#[N:18])=[C:11](F)[CH:10]=1.C(O)(=[O:23])C.C(OCC)(=O)C>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:12]([C:15](=[O:19])[C:16]3[C:17]([O:23]2)=[N:18][CH:3]=[CH:4][CH:5]=3)=[CH:13][CH:14]=1
Reactant: CN(C)/C=C/C=O
Reactant: CC(=O)O
Reactant: N#CCC(=O)c1ccc(Cl)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2ccc(Cl)cc2oc2ncccc12
Temperature: 25 °C
Yield: 10.2 %

Procedure:
A mixture of (E)-3-(dimethylamino)acrylaldehyde (3.26 g, 32.9 mmol), the product from Step 1 (5.00 g, 25.3 mmol) and acetic acid (7.24 mL, 127 mmol) in DMF (40 mL) was heated to 120° C. for 48 h and cooled to room temperature. Ethyl acetate (400 mL) was added and the mixture washed with saturated NaHCO3 (40 mL), water (40 mL), brine (40 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 10-40% ethyl acetate in hexanes) to provide 8-chloro-5H-chromeno[2,3-b]pyridin-5-one (600 mg, 10%). MS (ES+) m/z: 232 (M+H).
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][C:8]#[CH:9])[C:3]([OH:5])=O.[NH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]O.O>C1(C)C(C)=CC=CC=1>[F:1][CH:2]([C:3]1[O:5][CH2:12][C:11]([CH3:15])([CH3:14])[N:10]=1)[CH2:6][CH2:7][C:8]#[CH:9]
Reactant: CC(C)(N)CO
Reactant: C#CCCC(F)C(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: C#CCCC(F)C1=NC(C)(C)CO1
Yield: 56.8 %

Procedure:
A mixture of 2-fluoro-5-hexynoic acid (3.0 g, 23.05 mmol) and 2-amino-2-methyl-1-propanol (2.05 g, 23.05 mmol) in 150 ml of dry xylene was refluxed for 16 h. The water formed during the reaction was removed by Linde 3A molecular sieves (15 g) contained in a continuous extractor. The xylene was then distilled off at atmospheric pressure, and the resulting pot material was taken into ether (100 ml). The ethereal solution was washed with saturated sodium bicarbonate solution, water, and dried over MgSO4. Evaporation of ether at 35° C./~35 mm, and distillation of the resulting crude product gave 2.4 g (57%) of 2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole as a colorless liquid, bp 62°-66° C./0.6 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[C:10](N1C=CN=C1)(N1C=CN=C1)=[S:11].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[N:33]=[N:34][S:35][CH:36]=2)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:10](=[S:11])[NH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]2[N:33]=[N:34][S:35][CH:36]=2)=[O:31])=[CH:27][CH:28]=1
Reactant: Nc1ccc(NC(=O)c2csnn2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(NC(=S)Nc2cc(Cl)ccc2Cl)cc1)c1csnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is added freshly prepared 1,1′-thiocarbonyldiimidazole (0.20 g) and the mixture is stirred for appproximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture is stirred for approximately 6 hours. The solvent is then removed by evaporation under pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N#Cc1ccccc1N
Product: CCOC(=O)c1c(-c2ccccc2)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxo-3-phenylpropanoate as a yellow solid (45%). 1H NMR (400 MHz, DMSO-d6) δ 0.72 (t, J=8.0 Hz, 3H), 3.92 (q, J=8.0 Hz, 2H), 7.44 (m, 5H), 7.50 (m, 1H), 7.61 (bs, 2H), 7.73 (m, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H). MS 293 (MH+).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CC[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C(O)(=O)CCCC/C=C\C/C=C\C/C=C\C/C=C\CC>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:40]([OH:42])(=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]/[CH:32]=[CH:31]\[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCCC(=O)O
Agent: CC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(=O)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
A number of enzymes are involved in PUFA biosynthesis in addition to Δ5-desaturase and Δ6-desaturase. For example, elongase (elo) catalyzes the conversion of γ-linolenic acid (GLA) to dihomo-γ-linolenic acid (DGLA) and of stearidonic acid (18:4n-3) to (n-3)-eicosatetraenoic acid (20:4n-3). Linoleic acid (LA, 18:2-Δ9,12 or 18:2n-6) is produced from oleic acid (18:1-Δ9) by a Δ12-desaturase. GLA (18:3-Δ6,9,12) is produced from linoleic acid by a Δ6-desaturase.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:16]=[C:15]([C:17](O)=O)[CH:14]=[CH:13][N:12]=1>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:17]([C:15]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:10])[CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: Cc1cc(C(=O)O)ccn1
Solvent: O
Product: Cc1cc(-c2nc3cc(Br)cnc3[nH]2)ccn1
Reaction time: 16 h

Procedure:
0.30 g 5-bromo-2,3-diaminopyridine and 0.212 g 2-methyl-pyridine-4-carboxylic acid were heated in 3 g polyphosphoric acid at 160° C. with stirring for 16 hrs. The mixture was diluted with water and insoluble components removed by filtration. Water was evaporated from the filtrate and the residue dispersed in pyridine. Again, insoluble components were removed by filtration and the filtrate evaporated. The obtained residue was washed thoroughly with water and dried.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[N:52]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:18]([N:60]2[CH2:61][CH2:62][CH:57]([N:52]3[CH2:56][CH2:55][CH2:54][CH2:53]3)[CH2:58][CH2:59]2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 0.42 g (1.5 mmol) of 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (intermediate 1B) in 15 ml of DMF was added 0.60 g (1.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.62 ml=0.45 g (4.5 mmol) of Et3N; after 30 min, 0.24 g (1.6 mmol) of 4-pyrrolidin-1-yl-piperidine was added. 1 hour later, the reaction mixture was poured into crashed ice and extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 95:5 to 4:1) to give 0.56 g (89%) of the title compound as light brown oil. MS: 418.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH2:14]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH:14][CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CN
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1cc(F)ccc1C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone (20 mL) was added a 40% aqueous solution of methylamine (4.5 mL, 60 mmol) under nitrogen and the mixture stirred for 5 min. Acetone was removed in vacuo and the aqueous residue extracted with CH2Cl2. The CH2Cl2 extract was dried (Na2SO4), filtered, concentrated and the residue purified by column chromatography (SiO2, 10% ether in CH2Cl2) to provide 3.9 g (19.2 mmol, Yield 96%) of the title compound as a white solid; 1H NMR (500 MHz, CDCl3) δ ppm: 2.59 (3H, s), 2.67 (3H, d, J=5.5 Hz), 4.41 (1H, brs), 7.13–7.20 (1H, m), 7.29 (1H, dd, J=8.2, 5.5 Hz), 7.69 (1H, J=8.6, 2.1 Hz); LC/MS m/z 204 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:5]([NH:6][C:7](=[O:12])[CH2:8][O:9][CH2:10][CH3:11])[C:4](OCC)([N+:15]([O-])=O)[CH:3]=1.[H][H].[CH2:23]([OH:25])[CH3:24]>[Ni]>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[CH:8]([O:9][CH2:10][CH3:11])[O:25][CH2:23][CH3:24])=[C:4]([NH2:15])[CH:3]=1
Reactant: CCOCC(=O)NC1C=CC(Cl)=CC1(OCC)[N+](=O)[O-]
Reactant: [H][H]
Reactant: CCO
Agent: [Ni]
Product: CCOC(OCC)C(=O)Nc1ccc(Cl)cc1N

Procedure:
0.8 g of Raney-nickel are placed in a hydrogenation flask and suspended in 50 ml of ethanol. 7.6 g of 4'-chloro-2,2'-diethoxy-2'-nitroacetanilide are added thereto and the mixture is hydrogenated at room temperature and normal pressure. The uptake of hydrogen has finished after 2 hours. After suction filtration and concentration of the filtrate, the product is precipitated with water. There is obtained 4'-chloro-2,2-diethoxy-2'-aminoacetanilide of melting point 89°-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.[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>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(C#Cc2cccc(N)c2)ccn1
Temperature: 70 °C
Yield: 15.5 %

Procedure:
tert-Butyl (4-bromopyridin-2-yl)carbamate (1.935 g, 7.09 mmol), copper(I) iodide (0.67 g, 3.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.28 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.09 mL, 7.82 mmol) under N2 at rt. 3-Ethynylaniline (0.815 mL, 7.79 mmol) was added and the mixture was heated at 70° C. for 2 hours and only very little product was observed. Thus more 3-ethynylaniline (0.41 mL, 3.9 mmol) was added and the mixture was heated at 70° C. over the weekend. The reaction mixture was filtered and concentrated to give a brown residue, which was purified by silica gel column chromatography to give the desired product (340 mg, 16%). LCMS for C18H20N3O2 (M+H)+: m/z=310.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN([CH:16]=[C:17]1[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:18]1=[O:24])C>CCO>[O:23]=[C:22]1[CH2:21][CH2:20][CH2:19][C:18](=[O:24])[C:17]1=[CH:16][NH:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NNC=C2C(=O)CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
According to Scheme 3 Step 1: 4-Methylbenzenesulfonohydrazide (44.6 mmol, 8.31 g) was added to a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (44.6 mmol, 7.46 g) in EtOH (50 mL) and the reaction mixture was stirred at room temperature for 5 minutes. After evaporation, 13.8 g (44.6 mmol, 100%) of N′-((2,6-dioxocyclohexylidene)methyl)-4-methylbenzenesulfonohydrazide were obtained as an orange oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C(=O)C>[N:15]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:4]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)COc1cccc(CCl)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=NCc1cccc(OCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 122.3 %

Procedure:
A mixture of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.35 g, 1.55 mmol, Step-4) and sodium azide (0.20 g, 3.10 mmol) in N,N-dimethylacetamide (8 mL) is stirred 90° C. for 1 hour. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/ethyl acetate (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. The organic fraction is concentrated in vacuo to give 0.44 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-6) without further purification.
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.S(Cl)(Cl)=O.[NH3:20]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:20])=[O:12])=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 50 °C

Procedure:
20 g of 5-(3,4-dibromobutyl)picolinic acid was added to 15 ml of thionyl chloride and resulting solution was kept to warm at 50°C for one-half hour. Reaction mixture was evaporated in reduced pressure and resulting oily residue was dissolved in chloroform 100 ml. Through the solution dry ammonia gas was passed for five minutes with cooling. White precipitate was removed by filtration and washed with chloroform. Filtrate and washings are combined and evaporated in reduced pressure. Resulting solid was crystallized from benzene to give 10.2 g of the pure product as platelets.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(N(CC)CC)C.[C:20]([O:24][O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](Cl)=[O:30])([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>CCCCC.C(OC)(C)(C)C>[CH3:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:29](=[O:30])[CH2:28][CH2:27][C:26]([O:25][O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:32])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CN1C(C)(C)CC(OC(=O)CCC(=O)OOC(C)(C)C)CC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.2 %

Procedure:
Into a 500 ml flask equipped with a magnetic stirbar, thermometer, addition funnel, and nitrogen atmosphere sparger were placed 7.6 g (0.044 mole) of 1,2,2,6,6-pentamethyl-4-piperidinol, 4.4 g (0.044 mole) of triethylamine, and 100 ml of pentane. The addition funnel was charged with 9.7 g (0.044 mole) of 4-t-butylperoxy-4-oxobutanoyl chloride, 50 ml of methyl t-butyl ether and 50 ml of pentane. The acid chloride was added dropwise to the reaction mixture at a rate maintaining the temperature of the reaction less than 27° C. (about 70 min. for complete addition). After this addition, the reaction mixture was allowed to stir at ambient temperature for 45 minutes. To the mixture 100 ml of 5% aqueous sodium hydroxide (chilled to 5° C.) was then added with rapid stirring. The mixture was transferred to a separatory funnel with 100 ml of methyl t-butyl ether and 100 ml of pentane. The funnel was shaken and allowed to separate; and the aqueous phase was drawn off. The organic phase was extracted with 100 ml of aqueous 5% sodium hydroxide (chilled to 5° C.), and twice with 100 ml portions of cold (5° C.) water. The organic solution was dried with anhydrous sodium sulfate and the solvent was stripped using aspirator and high vacuum systems. The residue was transferred to a flask with 30 ml of pentane and treated with 5.3 g of decolorizing carbon (occasional swirling for 90 minutes). The mixture was diluted with 200 ml of pentane, filtered free from carbon, and stripped of solvent using aspirator and high vacuum. The product was a yellow oil weighing 9.7 g. Analysis showed an assay of 96.1% and corrected yield of 62.2%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[CH:22]=[CH:23][C:24]([N:28]([CH3:30])[CH3:29])=[N:25][C:26]=1[CH3:27])=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([CH3:27])=[N:25][C:24]([N:28]([CH3:29])[CH3:30])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: Cc1nc(N(C)C)ccc1N=C=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(N(C)C)nc2C)c1NCCCO
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.13 g, 4.38 mmol) and 5-isothiocyanato-N,N,6-trimethylpyridin-2-amine (1.27 g, 6.57 mmol) in tetrahydrofuran (15 mL) was stirred at 65° C. for 3 days. The mixture was concentrated in vacuo, and the residue was washed with ethyl acetate/diisopropyl ether to give methyl 4-chloro-3-({[6-(dimethylamino)-2-methylpyridin-3-yl]carbamothioyl}amino)-2-[(3-hydroxypropyl)amino]benzoate as a brown amorphous (1.09 g).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(OCC)C>[Br-:20].[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25])[CH3:28]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CCOCC
Product: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 100 °C

Procedure:
A mixture of triphenylphosphine (24.6 g; 0.0936 mol) and ethyl 4-bromobutyrate (from Aldrich Chemical Company, Milwaukee, Wis.) (14.4 mL; 0.101 mol) was heated from room temperature to 105° C. over a period of 15-20 minutes, and continued heating the resultant solution at 105° C. for 10 minutes. Allowed the solution to cool, but while still warm cautiously added diethyl ether (50 mL) via a condenser. Triturated the resultant gum to obtain a white powder. Decanted, added fresh diethyl ether (50 mL), and continued trituration for 10 min. Filtered the reaction mixture; washed the filter cake with diethyl ether; and under vacuum removed solvent from the combined filtrate and washings to obtain a mixture of oil and solids. Heated this mixture to 100° C.; cautiously treated with diethyl ether (2×55 mL); and repeated the trituration, filtration, and concentration sequence described above. Combined the two batches of white solids obtained from this process, triturated with toluene (150 mL), filtered, washed the collected solids with toluene and dried under high vacuum to obtain the title salt (11). FABMS 377 (M+) mp 177-179° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C(=O)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39](SC)=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:26][CH:25]=1>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:9][CH2:10]3)=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:26][CH:25]=1
Reactant: CSc1nc2cncnc2n1Cc1ccc(F)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(Cn2c(OC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 12.6 parts of 1-(phenylmethyl)-4-piperidinol, 3.2 parts of a sodium hydride dispersion 50% and 200 parts of N,N-dimethylacetamide was stirred for 1 hour at room temperature. 18 Parts of 9-[(4-fluorophenyl)methyl]-8-(methYlthio)-9H-purine were added portionwise and upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered off and taken up in trichloromethane. The organic layer was washed with water and filtered over diatomaceous earth. The filtrate was dried, filtered and evaporated. After crystallization from acetonitrile, the product was filtered off and dried, yielding 16.75 parts (61.1%) of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine; mp. 117.0° C. (compound 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Reactant: CC(C)(C)[Mg]Cl
Product: COc1cc2c(cc1C)C(C(C)(C)C)=CCC2(C)C
Yield: 9.7 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 30, 2.0 g, 9.2 mmol) was reacted with a solution of 2M tert-butylmagnesiumchloride (46 mL, 92.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.23 g (10%) of the title product as a yellow oil.