Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[Si:20]([NH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](NCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzenemethanamine (21.8 mL, 0.20 mol) and triethylamine (41.2 mL, 0.30 mol) in acetonitrile (400 mL) was added dropwise t-butylchlorodiphenylsilane (52 mL, 0.20 mol). The mixture was stirred at room temperature for 3 hours and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in a 4:1 mixture of ether/hexane and washed sequentially with H2O, saturated NaHCO3 solution and H2O. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave an oil which was distilled under high vacuum. The major fraction consisting of the pure product (45.9 g, 66%) distilled from 140° to 160° C. at about 0.1-0.2 mm Hg and crystallized on standing at room temperature, m.p. 34°-36° C.
Reaction SMILES: [I:1]CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCCC(C)C)C1.S([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C@H:55]1[CH2:72][CH2:71][C@@:70]2([CH3:73])[C:57](=[CH:58][CH2:59][C@@H:60]3[C@@H:69]2[CH2:68][CH2:67][C@@:65]2([CH3:66])[C@H:61]3[CH2:62][CH2:63][C@@H:64]2[C:74]([O:76][CH3:77])=[O:75])[CH2:56]1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O>>[I:1][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C@H:55]1[CH2:72][CH2:71][C@@:70]2([CH3:73])[C:57](=[CH:58][CH2:59][C@@H:60]3[C@@H:69]2[CH2:68][CH2:67][C@@:65]2([CH3:66])[C@H:61]3[CH2:62][CH2:63][C@@H:64]2[C:74]([O:76][CH3:77])=[O:75])[CH2:56]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of 17β-carbomethoxy-androst-5-en-3β-yl 6-iodohexyl ether, there was prepared 6-(17β-carbomethoxy-androst-5-en-3β-yloxy)-hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data and Rf values are given in the above Table.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([Cl:10])[N:6]=[N:5][C:4]=1[Cl:11].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(Cl)Cl>[CH2:12]([NH:19][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([Cl:10])[N:6]=[N:5][C:4]=1[Cl:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)nnc(Cl)c1CBr
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Cl)nnc(Cl)c1CNCc1ccccc1
Temperature: 90 °C
Yield: 97.7 %

Procedure:
To a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (500 mg, 2.82 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (503 mg, 2.82 mmol), and AIBN (2.3 mg, 0.014 mmol) in a round bottom flask equipped with condenser. The reaction was continuously irradiated with a 300 W light and refluxed for 5 h. The formed succimide was filtered and the filtrate was concentrated to afford 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine as a brown solid. To a solution of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (400 mg, 1.56 mmol) in DMF was added with benzyl amine (188 μL, 1.72 mmol) and TEA (326 μL, 2.34 mmol). The reaction mixture was heated at 90° C. for 2 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford a brown oil. The crude material was purified by flash chromatography on silica gel, eluting with 30-80% EtOAc:heptane. Fractions containing the desired product were combined and concentrated to afford a the title compound as a greasy solid (430 mg, yield: 54% (two steps)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2=O)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(F)cc(N2CCCC2=O)c1
Temperature: 65 °C
Yield: 28.8 %

Procedure:
A mixture of 2-[3-fluoro-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (130 mg, 0.34 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), 4-dimethylaminopyridine (62 mg, 0.51 mmol), methane sulfonamide (97 mg, 1.02 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{2-[3-fluoro-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (45 mg, 29%) as a light yellow solid: LC/MS m/e calcd for C23H26FN3O4S (M+H)+: 460.5, observed: 460.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].O[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: OCCN1CCOCC1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(O)cc4)ccc(F)c32)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCCN5CCOCC5)cc4)ccc(F)c32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 7, 140 mg, 0.29 mmol), N-(2-hydroxyethyl)morpholine (42 mg, 0.32 mmol), and triphenylphosphine (84 mg, 0.32 mmol) are suspended in dry tetrahydrofuran (5 mL) and cooled to 0° C. Di-tert-butyl azodicarboxylate (74 mg, 0.32 mmol) is added, the mixture is stirred for 2 hours at 0° C. then 2 h at room temperature. The solvent is removed under vacuum and residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound. (Yield 175 mg, 55% content). LC (METHOD 6): tR=0.57 min; Mass spectrum (ES+): m/z=562 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:20][C:21]1([CH3:24])[CH2:23][S:22]1>CO>[SH:22][C:21]([CH3:24])([CH3:23])[CH2:20][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: OCc1cc(CO)cc(CS)c1
Reactant: CC1(C)CS1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
(5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].C1(C)C=CC=CC=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN(C)C)c(C=O)c1

Procedure:
2-Hydroxy-5-methoxybenzaldehyde (31.2 g) in 170 ml of dimethylformamide is treated first with 10.1 g of 50% sodium hydride, then with 160 ml of a 2 N toluene solution of 3-dimethylaminopropyl chloride, following the procedure described in Example 1A, yielding 34.1 g of the title compound, boiling point 149°-155° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:3]=1.[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:19][C:20]1[C:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:3]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: N#Cc1ccc(Cl)nc1NCc1cccc(F)c1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccc(-c2cc(F)ncc2Cl)nc1NCc1cccc(F)c1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
6-chloro-2-(3-fluorobenzylamino)nicotinonitrile (0.602 g, 2.30 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (1.21 g, 6.91 mmol), and sodium carbonate (2.99 mL, 5.99 mmol, 2M in H2O) were dissolved in DME (10.5 mL). The resulting solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.376 g, 0.460 mmol). The resulting reaction mixture was heated in the microwave at 120° C. for 10 min. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc/95 hexanes to 50 EtOAc/50 hexanes yielded 0.2689 g (33%) of 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-5-carbonitrile. LCMS (m/z): 357.2 (MH+), retention time=1.02 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](O)[CH:14]=[CH2:15]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:15][CH:14]=[CH2:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: C=CCO
Reactant: COc1cc(C(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(OC)c1
Yield: 75 %

Procedure:
In a manner analogous to Example 1(a), 5 g (30 mmoles) of 4-hydroxy-3-methoxybenzoic acid treated at 100° C. for 4 hours with 50 ml of allyl alcohol and 820 μl of concentrated sulfuric acid, give 4.65 g (75% yield) of the expected ester in the form of a slightly yellow oil.
Reaction SMILES: [CH2:1]1COCC1.C[O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl>[CH3:1][N:13]1[C:8](=[O:7])[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:12]1
Reactant: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)cn1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Temperature: 85 °C
Yield: 53 %

Procedure:
To a stirred anhydrous THF (10 mL) mixture of N-({(5S)-3-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.10 g, 0.29 mmol) in a sealed tube, is added potassium carbonate (0.04 g, 0.58 mmol) and methyl iodide (0.1 mL, 1.7 mmol). The mixture is heated to 85° C. for 16 hours. The reaction is cooled to RT and diluted to 100 mL with CH2Cl2. The K2CO3 is filtered. The solution is concentrated to dryness, dissolved in MeOH (20 mL) and treated with saturated Na2S2O3. The solution is concentrated to dryness on silica. The residue is loaded onto a SIM and purified on a Biotage 12M column with 2–4% MeOH in CH2Cl2 to yield the desired compound (0.23 g, 53%). 1H-NMR (DMSO) δ: 8.26, 8.12, 7.82, 7.59, 6.47, 4.73, 4.14, 3.77, 3.50, 3.42, 1.84
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][CH:19]([OH:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:21][CH:19]([CH3:20])[CH3:18])[CH:3]=1
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 1.0 g of 4-chloro-2-fluoronitrobenzene and 9.3 g of caesium carbonate in 10 ml of 2-propanol is heated at 60° C. for 24 h. The mixture is then concentrated and the residue is taken up with 100 ml of a mixture of water and ethyl acetate. The aqueous phase is extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed with 50 ml of a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified on 90 g of silica, elution being carried out with 95/5 heptane/ethyl acetate, so as to obtain 885 mg of 4-chloro-1-nitro-2-(propan-2-yloxy)benzene in the form of a yellow solid.
Reaction SMILES: C(N1C2C(=CC(C)=CC=2)C(O)([CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)C1=O)C.C([O:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH3:46])[CH:44]=2)[N:39]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:38]1=[O:51])(=O)C1C=CC=CC=1>>[OH:36][C:37]1([CH2:13][C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH3:46])[CH:44]=2)[N:39]([CH2:47][CH:48]([CH3:49])[CH3:50])[C:38]1=[O:51]
Reactant: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CC(C)C
Reactant: CCN1C(=O)C(O)(Cc2cc(OC)c(OC)c(OC)c2)c2cc(C)ccc21
Product: COc1cc(CC2(O)C(=O)N(CC(C)C)c3ccc(C)cc32)cc(OC)c1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 5-methyl-1-isobutyl-2-oxoindolin-3-yl benzoate. 1H-NMR δ 7.22 (s, 1H), 7.08 (d, 1H), 6.58 (d, 2H), 6.1 (s, 2H), 3.74 (s, 3H), 3.63 (s, 6H), 3.48 (m, 1H), 3.29 (d, 1H), 3.11 (m, 1H), 3.06 (bs, OH), 2.35 (s, 3H), 1.85 (m, 1H), 0.70 (dd, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[N-:11]=[C:12]=[O:13].[Na+]>O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:12]([NH2:11])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCN(C(N)=O)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
N-Acetylpiperazine (25.0 g) was added to water (100 ml) and dissolved under stirring at ambient temperature. Then, the solution was adjusted to pH 3.0 with 6 N hydrochloric acid (about 33 ml). After the solution was cooled, sodium isocyanate (15.2 g) was added in one portion thereto at a temperature of 5 to 10° C. Thereafter, the mixture was reacted for 4 hours at ambient temperature and then cooled on ice to −2 to 2° C. The mixture was stirred at the same temperature for 2 hours to precipitate 4-acetyl-1-piperazinecarboxamide crystals. The crystals were collected at the same temperature by filtration, washed with cold water (25 ml) and dried under reduced pressure to give primary crystals of 4-acetyl-1-piperazinecarboxamide (17.7 g). The mother liquor containing the primary crystals was concentrated to 63 ml under reduced pressure and then stirred at −2 to 2° C. for 2 hours to precipitate secondary crystals of 4-acetyl-1-pipeazinecarboxamide. The crystals were collected at the same temperature by filtration, washed with cold water (13 ml) and dried under reduced pressure to give secondary crystals of 4-acetyl-1-piperazinecarboxamide (9.3 g). NMR (DMSO-d6, δ): 2.00 (3H, s), 3.21-3.41 (8H, m), 6.04 (2H, Broad s)
Reaction SMILES: CI.[C:3](O)(=O)C(O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH2:23][CH2:22][N:21]2[CH3:3])[CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CCC1)NCC2
Reactant: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CCC1)N(C)CC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of methyl iodide (0.5 g) in acetone (10 ml) was added dropwise to a stirred suspension of 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline oxalate (1.4 g prepared as described in Example RC11) and anhydrous potassium carbonate (3 g) in acetone (80 ml). The mixture was stirred at ambient temperature for 3.5 hours and the solvent removed by evaporation. Water was added and the mixture extracted with ether. The ether layer yielded 1-[1-(2-chloro-phenyl)cyclobutyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:21][N:22]=1
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(Br)cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (28 g, 81.4 mmol) in EtOH (100 mL) was added hydrazine hydrate (98%, 13.1 g, 162.8 mmol). The reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×10 mL) to give 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (22.0 g, 74.3 mmol, 92%). 1H NMR (DMSO-d6, 400 MHz): δ 10.83 (s, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.82 (q, J=6.8 Hz, 1H), 4.62 (d, J=13.2 Hz, 2H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CBr)n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1ccccc1)CO2
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2ccccc2)CO3)n1

Procedure:
By the method of Example 5, 500 mg (1.96 mmol) of trans-3-benzyl-4,6-chromandiol and 401 mg of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using 1:1 ethyl acetate:hexane as eluant to yield 0.38 g (53%) of present title product as white crystals, m.p. 87-90° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: Brc1ccc2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a stirred solution of 5-bromo-3H-imidazo[4,5-b]pyridine (1 g, 5.05 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 222 mg 5.56 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.39 g, 6.06 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt and stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.02 g, 52%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.43 (dd, J=1.5, 8.3 Hz, 1H), 5.60 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7](=[O:15])[CH:6]=1.Br[CH2:23][C:24](=[CH2:30])[C:25](OCC)=[O:26]>O1CCCC1.[Zn].C1(C=CC(O)=CC=1)O>[CH2:23]=[C:24]1[C:25](=[O:26])[O:1][C:2]([CH2:3][O:4][C:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7](=[O:15])[CH:6]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:30]1
Reactant: C=C(CBr)C(=O)OCC
Reactant: O=C(COc1cc(=O)oc2ccccc12)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(COc2cc(=O)oc3ccccc23)(c2ccccc2)OC1=O
Temperature: 0 °C
Yield: 86.1 %

Procedure:
To a solution of 2a (0.84 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was refluxed under nitrogen atmosphere for 18 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound (0.90 g, 86.4%). mp: 212°-214° C.; IR(KBr) νmax : 1766, 1717, 1620; UV(CHCl3) νmax (log ε): 306 (3.89), 277 (4.10), 266 (4.14); 1H-NMR (CDCl3): δ3.33 (dt, 1H, 4'-H), 3.66 (dt, 1H, 4'-H), 4.26, 4.32 (two d, 2H, OCH2), 5.60 (s, 1H, 3-H), 5.79 (t, 1H, vinylic H), 6.42 (t, 1H, vinylic H), 7.20-7.61 (m, 9H, 5,6,7,8-H, and aromatic H). Anal. Calcd for C21H16O5 0.25H2O: C, 71.48; H, 4.71. Found: C, 71.37; H, 4.67.