Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[O:2]([C:10]1[CH:35]=[CH:34][C:13]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][CH:11]=1)[Si](C(C)(C)C)(C)C.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][Si:43]1(C2C=CC=CC=2)[CH2:48][CH2:47][CH:46]([CH:49]2[CH2:54][CH2:53][CH:52]([CH:55]=O)[CH2:51][CH2:50]2)[CH2:45][CH2:44]1.Br[CH2:64][C:65]([F:71])([F:70])[C:66]([F:69])([F:68])[CH3:67]>>[F:68][C:66]([F:69])([C:65]([F:71])([F:70])[CH3:64])[CH2:67][O:2][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][CH2:55][C@H:52]2[CH2:53][CH2:54][C@H:49]([C@H:46]3[CH2:45][CH2:44][Si@H:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[CH2:48][CH2:47]3)[CH2:50][CH2:51]2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COCCCCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Reactant: CC(F)(F)C(F)(F)CBr
Agent: [Br-]
Product: COCCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(OCC(F)(F)C(C)(F)F)cc3)CC2)CC1

Procedure:
The general procedure of Example 38 was repeated using 4-(t-butyldimethylsiloxy)benzyltriphenylphosphonium bromide, 4-(4-(5-methoxy-n-pentyl)-4-phenyl-4-silacyclohexyl)cyclohexane carbaldehyde and 1-bromo-2,2,3,3-tetrafluoro-n-butane, thereby obtaining the intended compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH2:16][C@H:15]([C:17](O)=[O:18])[NH:14][C:13]3=[O:20])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C[Si](C)(C)CCON.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O>[OH:25][NH:26][C:17]([C@H:15]1[CH2:16][N:12]([CH2:11][C:10]2[CH:21]=[CH:22][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)=[CH:8][CH:9]=2)[C:13](=[O:20])[NH:14]1)=[O:18]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)CCON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NO)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4R)-l -[4-(4-fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid (120 mg, 0.36 mmol) in methylene chloride (5 mL) were added sequentially 1-hydroxybenztria zole (73 mg, 0.54 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol), O-(2-trimethylsilylethyl)hydroxylamine hydrochloride (92 mg, 0.54 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol). The reaction mixture was stirred at room temperature for 16 hours and was then diluted with methylene chloride and water. The organic phase was washed successively with aqueous 1M HCI solution, water, aqueous saturated NaHCO3 solution and brine. After drying over MgSO4, the solution was concentrated to an oil. The title compound, an oil (85 mg, 53%), was isolated by chromatography on silica gel eluting with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:12]([CH3:21])=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][C:16]=2[CH3:17])=[CH:5][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 6 %

Procedure:
To a solution of 4-methoxyphenol (6.70 g, 53.9 mmol) and 4-chloro-3,5-dimethyl nitrobenzene (10 g, 53.9 mmol) in N-methylpyrrolidinone (50 mL) at room temperature was added potassium carbonate (8.19 g, 59.3 mmol). The reaction mixture was heated to 125° C. and stirred for 20 hours. The solution was cooled to room temperature, diluted with water (500 mL), and extracted with methylene chloride (3 times 300 mL). The combined organic extracts were washed with potassium hydroxide (0.1N, 3 times 500 mL), water (500 mL), brine (500 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in a mixture of ether (20 mL) and petroleum ether (30 mL) and the title compound was crystalized as a brown solid (6.84 g). The mother liquor was concentrated and purified by column chromatography (20% methylene chloride in hexane to 27.5% methylene chloride in hexane) to give an additional product (0.88 g) and the unreacted starting material (3.4 g). 1H NMR (400 MHz, CDCl3) δ7.97 (s, 2H), 6.78 (d, 2H), 6.64 (d, 2H), 3.74 (s, 3H), 2.18 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].[BH4-].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[OH:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
The title compound of Example 2 (5.0 g, 13 mmol) was dissolved in THF (75 mL) and added dropwise over 20 minutes to a suspension of sodium borohydride (513 mg, 13 mmol) in 75 mL of ethanol at 0° C. and the reaction mixture was stirred for 3 hours at 0° C. The reaction mixture was poured onto ice-water (500 mL) and extracted twice with diethyl ether (700 mL). The organic extracts were combined and washed with water (250 mL), brine (250 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was recrystallized from hexane to afford 4.4 g (92%) of the racemic title compound. mp 82-83° C. 1HNMR (60 MHz, CDCl3): δ2.0 (m, 2H), 2.2 (s, 3H), 2.5 (t, J=6 Hz, 2H), 4.6 (m, 1H), 4.7 (broad s, 1H, hydroxyl proton), 7.1-7.5 (m, 7H), 7.8-8.0 (m, 2H).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36]([OH:38])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[N:49]1([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36](=[O:38])[N:52]1[CH2:53][CH2:54][N:49]([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:50][CH2:51]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCC(F)(C(=O)O)c1ccc(Cl)cc1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
PyBrop (562 mg, 1.21 mmol) was added in a single portion to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid (400 mg, 1.21 mmol) and 4-piperazin-1-yl-quinazoline dihydrochloride (346 mg, 1.21 mmol) in DCM (12 mL) cooled in an ice bath. DIEA (0.84 mL, 4.82 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was diluted with DCM and washed with 0.1N HCl. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using 2% MeOH/DCM followed by 5% MeOH/DCM as eluent to give [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (230 mg). LCMS (APCI+) m/z 528, 530 [M+H]+.
Reaction SMILES: C([Mg]Br)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:12](=[S:14])=[S:13].Br[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:17]#[N:18]>O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:12]([S:14][CH:16]([C:17]#[N:18])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:13])=[CH:7][CH:6]=1
Reactant: N#CC(Br)c1ccccc1
Reactant: COc1ccc(C[Mg]Br)cc1
Reactant: S=C=S
Solvent: O
Product: COc1ccc(C(=S)SC(C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml round bottom flask was added 20 ml p-anisylmagnesium bromide (0.49M solution in ethyl ether). 0.76 g carbon disulfide was added dropwise to this mixture and stirred for ½ h at room temperature. Then to the dark red solution was added 2 g α-bromobenzeneacetonitrile dropwise and the mixture stirred for another 2 h. Water was added to the mixture and the organic product was extracted with diethyl ether (3×50 ml), dried with magnesium sulfate overnight and filtered. After removal of solvent and column chromatography (5:1 mixture of hexane and ethyl ether), pure α-cyanobenzyl 4-methoxydithiobenzoate was obtained as an orange odorless solid (73% yield). Proton and carbon NMR spectra were consistent with the expected structure, CTA-CP-3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2].[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:35](=[O:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Temperature: 25 °C
Yield: 8.9 %

Procedure:
A mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (4.35g, 9.86 mmol), phenylacetyl chloride (4.0 mL, 30 mmol) in two portions and tin (IV) chloride (4.3 mL, 37 mmol) in chloroform (220 mL) was refluxed for five hours. It was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. After stirring the residue in ether and filtering, the filtrate was concentrated and purified by flash chromatography using (1) 25–35% methylene chloride in hexane and 100% methylene chloride and (2) 1–8% ethyl acetate in hexane. It was then purified by HPLC using 85% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for one hour yielded [1-bromo-6-(3-phenylacetyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester as a yellow semi-solid (0.491 g, 8.89%); mass spectrum (+EI, [M+H]+) m/z 559/561. 1H NMR (500 MHz, DMSO-d6): δ8.28 (d, 1H, J=7.19 Hz), 8.17 (d, 1H, J=1.98 Hz), 8.12 (d, 1H, J=9.01 Hz), 8.06–8.10 (m, 1H), 7.90–7.93 (m, 1H), 7.81 (dd, 1H, J=8.78 Hz and 1.91 Hz), 7.54 (d, 1H, J=9.16 Hz), 7.45–7.50 (m, 2H), 7.13–7.19 (m, 3H), 6.91–6.94 (m, 2H), 5.13 (s, 2H), 4.19 (q, 2H, J=7.13 Hz), 3.81 (s, 2H), 1.22 ppm (t, 3H, J=7.10 Hz). Elemental Analysis for C30H23BrO4S+0.10 mol H2O: Calcd: C, 64.19; H, 4.17; N, 0.00; Found: C, 63.85; H, 4.03; N, 0.00.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]>O1CCCC1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCCO)ccc1Cl
Temperature: 60 °C

Procedure:
4-Amino-1-butanol (0.11 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.25 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25-95%) gave the title compound as the acetate salt. Treatment with aqueous 2M sodium hydroxide and extraction into ethyl acetate gave the title compound (0.065 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][NH:13][CH:14]1[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]([CH3:12])[CH:14]1[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CNC1CCN(C)C1
Solvent: CCOC(C)=O
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2Cl)C1
Reaction time: 24 h

Procedure:
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N′-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[Cl:20].[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:13][C:7]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([Cl:20])[C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([CH:29]=[O:30])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)c2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: -72 °C
Reaction time: 0.33 h

Procedure:
A yellow solution of 6-bromo-2,4-dichloro-8-fluoro-3-phenylquinoline (1.01 g, 2.72 mmol, Intermediate 46, step a) in THF (10 mL) was stirred at −72° C. while n-BuLi (1.15 mL, 2.59 M in hexane, 2.99 mmol) was added dropwise under argon. The resulting homogeneous dark solution was stirred at −72° C. for 20 min, and was then treated with DMF (0.273 mL, 3.53 mmol) dropwise. The homogeneous dark reaction was stirred at −72° C. for 25 min, and was then removed from the cold bath and stirred under ambient conditions for 30 min. The dark homogeneous solution was quenched with 5 M NH4Cl (10 mL) and the aqueous layer was extracted with EtOAc (3×8 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a 20% DCM/heptane to 100% DCM gradient to provide the title compound as a yellow powder.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.S(Cl)([Cl:39])=O.O.C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Cl:39][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 816 mg of 4-hydroxymethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole prepared in step e) in Example 1 in 25 ml of THF was cooled in ice, and 0.301 ml of triethylamine and 0.157 ml of thionyl chloride were added to the cooled solution under an argon atmosphere. The mixture was stirred at the same temperature for 20 min, brine was then added to the reaction solution, and the mixture was adjusted to pH 8 by the addition of sodium bicarbonate water. The mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) to give 512 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=1)[CH3:17]>>[ClH:15].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Agent: Cl
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyrimidyl) piperazine dihydrochloride instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as a yellow amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)c1ccccc1
Yield: 44.6 %

Procedure:
Using the general method of Example 186 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.84 g, 2.27 mmol) was reacted with benzoyl choride (260 μL, 2.27 mmol) to provide 0.48 g of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzamide as a tan powder, m.p. 133.4-137.5° C. Analysis: Calculated for C28H35N5O2: % C, 71.01; % H, 7.45; % N, 14.79. Found: % C, 71.41; % H, 7.35; % N, 14.48.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:21][CH2:22][O-:23].[Na+]>C(O)C>[CH2:22]([O:23][C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1)[CH3:21]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1c(C)nn(C)c12
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn2c1c(OCC)nc1c(C)nn(C)c12

Procedure:
5.86 gms. of 5-chloro-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, in ethanol is refluxed with 20 mM of sodium ethylate for 30 minutes. Upon cooling, the product, 5-ethoxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, crystallizes in the form of white needles. The product is recrystallized from n-propanol, yield 4.2 gms, m.p. 116°-118°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[CH:3][CH:4]=3)[C:16]=12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(-c2nn([C@@H]3CCOC3)c3ncnc(N)c23)cc1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.075 g, 0.25 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.035 mL, 0.25 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD68. ESI-MS m/z [M+H]+ found 469.4, calculated 469.2.
Reaction SMILES: I[C:2]1[N:22]=[CH:21][C:5]2[N:6]=[CH:7][N:8]([CH2:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][C:39]#[CH:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.[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>[C:32]1([CH2:38][C:39]#[C:40][C:2]2[N:22]=[CH:21][C:5]3[N:6]=[CH:7][N:8]([CH2:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=4)[C:9](=[O:10])[C:4]=3[CH:3]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C#CCc1ccccc1
Reactant: O=C(O)c1ccc(Cn2cnc3cnc(I)cc3c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cn2cnc3cnc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 50 °C

Procedure:
To a solution of the compound obtained in Step 1 (0.739 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), CuI (catalytic amount), 3-phenyl-1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is warmed to 50° C. for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3×100 ml of water, 1×100 ml of brine. The organic layer is then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo. The crude product is triturated with 8/1: hexane/EtOAc to yield the desired compound.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[CH:5]=[CH:6]/[CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH:11]([CH:13]=C)=[O:12].[CH3:15]C(C1C=C(O)C=CC=1OC)(C)C.CC(C1C=C(OC)C=CC=1O)(C)C>>[CH3:4][C:3]1[CH:2]([CH3:15])[CH2:1][CH:13]([CH:11]=[O:12])[CH:6]([CH:7]=[C:8]([CH3:10])[CH3:9])[CH:5]=1
Reactant: C=CC=O
Reactant: COc1ccc(O)cc1C(C)(C)C
Reactant: C/C=C(C)/C=C/C=C(C)C
Agent: COc1ccc(O)c(C(C)(C)C)c1
Product: CC(C)=CC1C=C(C)C(C)CC1C=O
Yield: 70 %

Procedure:
554 g of allo-ocimene (85% 4E, 6Z; 15% 4E, 6E) and 224 g of acrolein were placed in a stainless steel vessel which is equipped to withstand a high internal pressure at elevated temperatures. 1 gm of embanox, a polymerisation inhibitor, was added. The air in the vessel was displaced with nitrogen and the vessel was closed. The temperature was raised to 165°-170° C. and maintained in the range for 6 hours. The maximum pressure recorded was 150 psi. The reaction mixture was then distilled and a mixture of four isomeric aldehydes collected which represented a 70% yield of the desired product. The percentages of adducts were determined by GLC to be as follows: ##STR6##