Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:11]2[C:6]([C:7]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1.[C:23]([S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:26])([CH3:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[C:23]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([N:18]2[CH2:17][CH2:16][C:7]3([C:6]4=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[N:11]4[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[O:8]3)[CH2:20][CH2:19]2)=[O:35])=[CH:37][CH:38]=1)(=[O:29])=[O:28])([CH3:26])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reactant: CC(C)(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.5 %

Procedure:
1′-(Trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (172 mg, 0.559 mmol), 4-tert-butylsulfonylbenzoic acid (176 mg, 0.727 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (150 mg, 0.783 mmol), and triethylamine (312 μL, 2.24 mmol) were combined in dichloromethane (3.4 mL). The reaction mixture was allowed to stir for 72 hours at room temperature. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water to yield (4-tert-butylsulfonylphenyl)-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (49 mg, 16%) as a white solid. ESI-MS m/z calc. 532.2, found 533.5 (M+1)+. Retention time: 2.10 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.89 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=3.9 Hz, 1H), 4.53-4.37 (m, 1H), 3.57-3.14 (m, 3H), 2.17-1.78 (m, 4H), 1.26 (s, 9H).
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH2:33])[CH2:24]1)[CH:20]=[CH2:21].[O:34]1[CH2:36][C@@H:35]1[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=2)[C@@H:25]([NH:33][CH2:36][C@@H:35]([OH:34])[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:24]1)[CH:20]=[CH2:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(Br)ccc21
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c2cc(Br)ccc21
Yield: 82 %

Procedure:
Step BD (1). (1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-amine from Step Z(1) was reacted with tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (Aldrich) according to the procedures described in Step V (1) to afford, after purification, 275 mg (82% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. MS (M+H)+ 531.43. 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (s, 9H) 1.82 (ddd, J=12.67, 6.26, 6.10 Hz, 1H) 2.69-2.79 (m, 3H) 2.87 (dd, J=13.89, 8.09 Hz, 1H) 3.03 (dd, J=14.04, 4.58 Hz, 1H) 3.38-3.46 (m, 1H) 3.79 (s, 1H) 4.01-4.05 (m, 2H) 4.06-4.15 (m, 2H) 4.54 (d, J=9.16 Hz, 1H) 4.75 (t, J=6.10 Hz, 1H) 5.19 (dd, J=10.38, 1.53 Hz, 1H) 5.31 (ddd, J=17.24, 3.20, 1.53 Hz, 1H) 5.94 (ddd, J=22.74, 10.53, 5.49 Hz, 1H) 7.18-7.32 (m, 7H) 7.40 (d, J=8.24 Hz, 1H) 7.50 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3CCN(CC)CC3)[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(N(CC)CC)C.CC([OH:62])(C#C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:62])[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3sccc23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Yield: 109.5 %

Procedure:
6-(4-Bromophenyl)-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.96 g) was heated under reflux in the presence of bistriphenylphosphine dichloride (48 mg), triphenylphosphine (174 mg) and cuprous iodide (46 mg), in 2-methyl-3-butyn-2-ol (0.26 g), pyridine (15 ml) and triethylamine (30 ml) for 1.5 hr. The reaction solution was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.80 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1>>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([CH:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:14]1
Reactant: CC1=NC(C)(C)CO1
Reactant: O=Cc1ccccc1
Product: CC1(C)COC(C=Cc2ccccc2)=N1

Procedure:
4,4-Dimethyl-2-(2-phenylethenyl)-2-oxazoline (P-1886) was prepared by reacting benzaldehyde with 2,4,4,-trimethyl-2-oxazoline. The product had a boiling point of 112° at 0.45mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2)[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:27][N:3]1[CH2:4][CH:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]2([CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A diastereomeric mixture. of tert-butyl 1-oxo-4-phenyl-2,8-diazaspiro[4.6]undecane-8-carboxylate (step 4) (669.5 mg; 1.944 mmol) in THF (19.5 ml) under nitrogen was cooled in an ice/brine bath. 1M LHMDS (2.5 ml, 2.53 mmol) was added and the mixture was stirred at 0° C. for 40 minutes. Iodomethane (182 ul, 2.92 mmol) was added and the mixture was allowed to warm slowly to RT overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with EtOAc afforded the title compound;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17](C)C(Cl)=O.C[Si](C)(C)C#N.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:16]#[N:17])[CH:11]=[CH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(F)c1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution (40 mL) of 2-(3-fluorophenyl)-3-methylpyridine 1-oxide (4.26 g, 21.0 mmol), dimethylcarbamic acid chloride (2.94 g, 27.3 mmol) and trimethylsilanecarbonitrile (2.71 g, 27.3 mmol) in tetrahydrofuran was heated under reflux, and the mixture was stirred for 2 hr. After cooling to room temperature, the reaction solution was divided into two layers with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound (4.42 g, 99%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17]([CH2:2][C:3]2[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=2)[CH:18]=1
Reactant: Cc1ccc(CCl)nc1C#N
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)nc1C#N
Yield: 64 %

Procedure:
To a solution of 6-(Chloromethyl)-3-methyl-2-pyridinecarbonitrile (132.5 mg) in dry toluene (4 ml) and ethanol (4 ml) was added (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid (250 mg), potassium carbonate (330 mg) and tetrakis(triphenylphosphine)palladium(0) (92 mg) and the mixture stirred under reflux for 2.5 hours. Solvent was removed in vacuo and water (20 ml) and ether (20 ml) added. Insoluble solid was filtered over Celite and washed with ether. The aqueous layer was further extracted with ether (15 ml) and the combined extracts washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (204 mg, 64%) as a white solid.
Reaction SMILES: Br[C:2](Br)([CH2:5][CH3:6])[CH2:3][CH3:4].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[K].C([O-])(C)(C)C.Cl>C1(C)C=CC=CC=1>[C:8]1(=[O:14])[C:13]2([CH2:6][CH2:5][CH2:2][CH2:3][CH2:4]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCC(Br)(Br)CC
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1CCCCC12CCCCC2

Procedure:
Dibromopentane (5 mmol) is added to a solution of cyclohexanone (5 mmol) and potassium-tert-butanolate (10 mmol) in toluene (7.5 ml) and the reaction mixture is refluxed for 48 hours. After cooling to room temperature 25% hydrochloric acid is added and extraction is carried out with diethyl ether. The combined organic phases produce, after drying over sodium sulphate, removal of the solvent in a vacuum and chromatography of the residue using silica gel (ethyl acetate/heptane, 1:5) pure spiro[5.5]undecan-1-one (Tetrahedron 1964, 20, 2553-2573): tR 1.90 min. (LC-2); ESI-MS (+): m/z 167.27 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([O:25][CH:26]([F:28])[F:27])=[N:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.[H][H]>[Pd].C1COCC1>[F:28][CH:26]([F:27])[O:25][C:13]1[C:12]2[C:16](=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=2)[N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[N:14]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Tert-butyl 6-(benzyloxy)-3-(difluoromethoxy)-indazole-1-carboxylate (262.5 mg) which can be prepared according to the method described in Reference example 33, etc. and 5% palladium on carbon-STD-type-50% wet with water (109.9 mg; manufactured by N. E. Chemcat Corp.) were suspended in dehydrated THF (3.4 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (197.2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(CCO)C=CC=CC=1.O>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccs1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCc1ccccc1
Solvent: O
Product: O=C(O)c1cc2cc(-c3cccs3)ccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a sealed tube containing 2-[5-bromo-1-benzyl-1H-indole-2carboxylic acid (100 mg, 0.303 mmol) and 2-thiopheneboronic acid (116 mg, 0.909 mmol), (C6H5)4Pd (42 mg, 0.036 mmol), Na2CO3 (2,42 mmol) in a mixture of benzene-ethanol-H2O (5/1/2=v/v, 4.5 mL) was heated at 100° C. for 23 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The organic layer was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column (15% EtOAc in hexane with 1% HCOOH) to give 65 mg of the product.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(ON=O)CC(C)C.[I:20]CI>>[I:20][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc2ncccc12
Reactant: ICI
Agent: CC(C)CCON=O
Product: Ic1cccc2ncccc12
Temperature: 80 °C

Procedure:
A suspension of 10 g (0.07 mol) of 5- aminoquinoline, 94 ml (0.7 mol) of isoamylnitrite and 100 ml of diiodomethane was heated at 80° C. for 2 hours. The reaction mixture was evaporated under reduced pressure at 60°-70° C. The residue was slurried with diethyl ether, decanted and the filtrate was evaporated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with 3:1 hexane-ethyl acetate to yield 2.81 g of 5-iodoquinoline. 1H-NMR (CDC13, 300MHz) δ 7.42(d, 1H, J=7.7 Hz); 7.48 (dd, 1H, J=4.3 Hz); 8.1 (m, 2H,); 8.38 (d, 1H, J=8.5 Hz); 8.88 (m, 1H,). Mass spec. m/e=255=p. ##STR27## 2.18 g (0.022 mol) of triethylamine were added to a suspension of 2.75 g (0.011 mol) of 5-iodoquinoline in acetonitrile (24 ml) and the solution formed on warming. The solution was allowed to cool briefly. To the solution were added 50 mg of triphenylphosphine, 50 mg of palladium(II) acetate and 3.1 ml (0.022 mol) of 3,3- zdiethoxy-1-propyne (propiolaldehyde diethylacetal). The reaction was heated at 80° C. for 1.5 hours. The reaction was poured into water and extracted with hexane. The hexane was removed under reduced pressure and the residue was chromatographed on a silica gel column and eluted with 1% methanol-dichloromethane to yield 1.44 g of 5-quinoline-[l- propiolaldehyde diethyl acetal]. 1H-NMR (CDC13, 300MHz) 6 1.3 (t, 6H, J=7.2 Hz); 3.73 (m, 2H,); 3.88 (m, 2H); 5.62 (s, 1H,); 7.48 (dd, IH, J=8.5 and 4.2 Hz); 7.66 (d, 1H, J=7.4 Hz); 7.76 (d, 1H, J=7.2Hz); 8.1 (d, 1H, J=8.5Hz); 8.6 (d, 1H, J=8.5Hz); 8.94 (m, 1H). Mass spec. m/e=255=p. ##STR28##
Reaction SMILES: [OH-].[Li+].C(O)(=O)CS.CN(C=O)C.[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][N:34]([CH2:47][CH2:48][N:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:29]=[CH:30][C:16]1=2)[CH3:14]>O>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][NH:34][CH2:47][CH2:48][N:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCN(CCn3ccc4ccccc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCNCCn3ccc4ccccc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Lithium hydroxide (3.2 g), and thioglycolic acid (2.4 ml) were added to a DMF solution (27.4 ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide (4.56 g). The mixture was stirred at room temperature for 1 hour. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed under reduced pressure to produce the title compound (2.24 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]([OH:32])=[O:31])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: C=CC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.68 ml, 0.0049 mole), trimethyl silylchloride (0.61 ml, 0.0049 mole) and acrylic acid (0.175 g, 0.0024 mole). The reaction mixture was stirred at room temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water and sodium bicarbonate, dried over anhydrous sodium sulfate and the organic solvent removed on a rotavap to produce the title compound as a thick oil (0.4 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Br:29]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:29])[N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nc(Sc2ccc3ccccc3c2)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 44 %

Procedure:
6-Amino-9-benzyl-2-(2-naphthylthio)purine (221 mg, 0.58 mmol) and bromine (0.4 ml) were dissolved in 160 ml of methylene chloride and the solution was stirred at room temperature for 5.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (118 mg, yield 44%).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14]C(=O)C)[CH:13]=1)[CH:9]=O)(=O)C.[CH2:18]([SH:21])[CH2:19][SH:20].[OH-].[K+]>CCOCC>[S:20]1[CH2:19][CH2:18][S:21][CH:9]1[C:8]1[CH:7]=[C:6]([OH:5])[CH:13]=[C:12]([CH:11]=1)[OH:14]
Reactant: SCCS
Reactant: CC(=O)Oc1cc(C=O)cc(OC(C)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Oc1cc(O)cc(C2SCCS2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
Dry hydrogen chloride was bubbled into a solution of 50.0 g (0.23 mole) of 3,5-diacetoxybenzaldehyde and 21.4 g (0.23 mole) of 1,2-ethanedithiol in 25 ml of ether until the solution became warm. After allowing the solution to stand at ambient temperature for 0.75 hour, the solvent was removed in vacuo and excess methanol was added. A solid of 1,3-diacetoxy-5-(1,3-dithiolan-2-yl)benzene (mp 94°-96° C.) was separated by filtration. It was resuspended in 100 ml of methanol and 21.7 g (0.23 mole) of potassium hydroxide pellets were added. On stirring the mixture at ambient temperature for 0.5 hour, the mixture became homogeneous. The solvent was removed in vacuo and the residue after acidification with 6N hydrochloric acid was extracted with ethyll acetate. The extract was washed with water until neutral, dried and evaporated in vacuo to leave 5-(1,3-dithiolan-2-yl)resorcinol as a gum (41.3 g, 84%) which was used without further purification in the subsequent reaction. The structure was confirmed by the infrared and nuclear magnetic resonance spectra.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:34]=[CH:35][CH:36]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cccc(OCCCCBr)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cccc(OCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3-methoxyphenoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(4-(3-methoxyphenoxy)butyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][CH:2]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:14]I>O1CCCC1>[F:1][C:2]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([C:3](=[O:8])[C:4]([CH3:7])([CH3:5])[CH3:6])[CH3:14]
Reactant: CC(C)(C)C(=O)C(F)n1cncn1
Reactant: CI
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(C)(F)n1cncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
20.0 g of 1-fluoro-1-(1H-1,2,4-triazol-1-yl)-3,3-dimethyl-2-butanone are added dropwise to a solution of 13.5 g of potassium tertiary butylate in 100 ml of tetrahydrofuran. After the mixture has been stirred for 0.5 hour, 15.6 g of methyl iodide are added dropwise and the mixture is stirred for 18 hours at 60° C. After cooling, the reaction mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Distillation of the oily residue gives 14.0 g of 2-fluoro-2-(1H-1,2,4-triazol-1-yl)-4,4-dimethyl-3-pentanone, boiling point 48°-50° C./0.013 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8]Br.BrCC1C=C(Cl)C(CC2C=C(C(C)C)[C:23](=O)[NH:24]N=2)=C(Cl)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8][C:23]#[N:24]
Reactant: OCc1cc(Br)c(CBr)c(Br)c1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CBr)cc2Cl)n[nH]c1=O
Product: N#CCc1c(Br)cc(CO)cc1Br
Yield: 78 %

Procedure:
This compound was prepared by a similar method to that described in Example 14, Step 5 except that (3,5-dibromo-4-bromomethyl-phenyl)-methanol (58) was used in place 6-(4-bromomethyl-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (54). The product was purified by flash chromatography using silica gel eluted with a gradient of 3:1 to 1:1 hexanes:ethyl acetate. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 2,6-dibromo-4-hydroxymethyl-phenyl)-acetonitrile (59) (78%) as a yellow solid; EI(+)-HRMS m/z calcd for C9H7Br2NO (M+) 302.8894, found 302.8881. MW=304.9702, Exact Mass=302.8894