Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7].[C:34](=[O:37])([O-])[O-].[K+].[K+].[ClH:40]>CN(C)C=O.C(OCC)(=O)C>[ClH:40].[ClH:40].[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:3][C:4]#[C:5][CH2:6][N:8]2[CH2:13][CH2:34][O:37][CH2:10][CH2:9]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc2ccccc2c1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCOCC2)C[C@H]1Cc1ccc2ccccc2c1
Reaction time: 17 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine (200 mg) and 1-(4-chloro-2-butynyl)morpholine hydrochloride (95 mg) in N,N-dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (177 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2-butynyl)-2-(2-naphthylmethyl)piperazine dihydrochloride (257 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)#[N:20].CCOCC>CCOC(C)=O>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:22]2[C:21]([C:19]#[N:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: N#Cc1cccnc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N#Cc1cccnc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 3-cyanopyridine (0.25 g) was heated to 100° C. for 30 min. The reaction mixture was partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a solid which was stirred with 5 mL ether and 0.5 mL EtOAc for 1 h and filtered to give the title compound as a solid. M.S (M+1): 351
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[C:7]=3[OH:22])[S:12][N:13]=2)=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of 3-(4-Fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.47 mmol), glycine (1.06 g, 14.1 mmol), and NaOMe (23.5 mL, 11.75 mmol, 0.5 M solution in MeOH) was refluxed for 24 h. After cooling to r.t. the mixture was concentrated in vacuo. The residue was dissolved in water (50 mL), and the solution washed with CH2Cl2 (2×30 mL) before it was acidified by addition of aqueous 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound (146 mg) as white solid: MS (m/z) 346.1 (M−1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])(=[O:34])=[O:33]>>[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:43])=[O:42])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
2-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-methylsulfonylbenzenesulfonylchloride (61 mg, 0.239 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 551.2; Calcd: 551.10; 1H-NMR δ 8.36-7.46 (m, 9H), 6.95 (d, 1H), 6.68 (dd, 1H), 6.46 (d, 1H), 3.47 (s, 3H), 3.28-3.17 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Flash chromatography (silica gel, 15% ethyl acetate-hexane) afforded the title compound (2.12 g, 84%) as a white solid; 1H NMR (300 MHz, CDCl3) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>CCO>[CH3:12][C:2]1[S:15][C:14]([NH2:16])=[N:13][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(C(=O)C(C)Br)cc1
Solvent: CCO
Product: Cc1ccc(-c2nc(N)sc2C)cc1
Yield: 98.5 %

Procedure:
A mixture of 2-bromo-1-(p-tolyl)propan-1-one (6.88 g, 30.3 mmol) and thiourea (2.54 g, 33.4 mmol) in 95% EtOH (43 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 5-methyl-4-(p-tolyl)thiazol-2-amine (6.10 g) as white solids in 99% yield: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.18 (bs, 2H), 2.37 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CN1CCC(N2CCc3ccc(N)cc32)CC1
Reaction time: 8 h

Procedure:
1-(1-Methyl(4-piperidyl))-6-nitroindoline (3 g) was dissolved in 100 mL MeOH and the mixture was bubbled with H2 for 10 min. 10% Pd/C (200 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford light yellow oil. MS: 232 (M+1). Calc'd. for C14H21N3—231.3.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31][C:32](O)=[O:33]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][C@H:27]5[CH2:28][CH2:29][CH2:30][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C[C@H]1CCCO1
Agent: Cl
Product: O=C(C[C@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (34 mg, 62%), MS (ISP) m/z=443.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.124 mmol) and (R)-2-(tetrahydrofuran-2-yl)acetic acid
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25](Br)=[C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH:27]=3)[C:22]([CH3:38])([CH3:37])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH:27]=3)[C:22]([CH3:38])([CH3:37])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cc(Br)c(CN3CCCC3=O)cc21
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(CN3CCCC3=O)cc21
Reaction time: 1 h
Yield: 113.5 %

Procedure:
10% Pd/C (12 mg, 0.1 mmol) and (2R,5R)-4-{2-[5-bromo-3,3-dimethyl-6-(2-oxo-pyrrolidin-1-ylmethyl)-2,3-dihydro-indol-1-yl]-2-oxo-ethyl}-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (66 mg, 0.1 mmol) were dissolved in methanol (0.44 mL) and triethylamine (23 μL, 0.16 mmol) was added. The reaction was hydrogenated at 1 bar for 1 h at ambient temperature then filtered under vacuum and concentrated. Residue was dissolved in methanol, loaded onto SCX column eluting with methanol then 2.0 M ammonia in methanol to release the amine and the relevant fractions concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (60 mg), MS: [M+H]+=529.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1cccc(CN)c1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: COc1cccc(CNc2ncnc3cc(N)ncc23)c1
Yield: 76.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (136 mg, 0.71 mmol) (described in a previous experimental) and 3-methoxybenzylamine (1.37 g, 10.0 mmol) in isopropanol (3 mL) is stirred under N2 at reflux for 3 h. Evaporation of the solvent and chromatography on silica gel (5-10% EtOH/EtOAc) gives 7-amino-4-(3-methoxybenzylamino)pyrido[4,3-d]pyrimidine (153 mg, 77%) as a white solid. 1H NMR (DMSO) δ 9.11 (1H, s), 8.83 (1H, t, J=5.7 Hz), 8.26 (1H, s), 7.24 (1H, dt, Jd=0.8 Hz, J5=8.1 Hz), 6.92 (2H, m), 6.81 (1H, dt, Jd=8.2 Hz, Jt=1.2 Hz), 6.46 (2H, brs), 6.37 (1H, s), 4.71 (2H, d, J=5.8 Hz), 3.73 (3H, s).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:28]4[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 1 but starting from 2.1 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 20 cm3 of pyridine and 2.4 g of 2-methylpiperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].[CH:15]12[O:20][CH:16]1[CH2:17][CH2:18][CH2:19]2.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[OH:20])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: C1CC2OC2C1
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(O[C@H]2CCC[C@@H]2O)cc1F
Temperature: 70 °C
Reaction time: 14 h
Yield: 54.8 %

Procedure:
To a solution of compound (8) (3.50 g, 17.7 mmol) in dry DMF (35 mL), cyclopentene oxide (2.3 mL, 26.6 mmol) and sodium hydride (0.64 g, 26.6 mmol) were added and stirred at 70° C. for 14 hours. After completion of the reaction, the obtained mixture was cooled to room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate (300 mL) followed by washing with water and drying (over sodium sulfate). The solvent was distilled off, and the residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (8:1) solution followed by conventional hydrolysis to give 2.60 g (52%) of compound (13) of interest as yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[N:12]([C:13]3[O:14][C:15]4[C:16](=[C:18]([C:22]([OH:24])=O)[CH:19]=[CH:20][CH:21]=4)[N:17]=3)[CH2:11][CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:27][C@H:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:29][CH:28]([NH:27][C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:15]4[O:14][C:13]([N:12]5[CH2:11][CH2:10][O:9][CH2:8][C@@H:7]5[C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:17][C:16]=34)=[O:24])[CH:33]([CH2:34][CH2:35]1)[CH2:32][CH2:31]2
Reactant: O=C(O)c1cccc2oc(N3CCOCC3c3ccccc3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(N3CCOC[C@@H]3c3ccccc3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-(3-phenylmorpholino)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(3-phenylmorpholino)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[C:19]2[CH:18]=[CH:17][S:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>ClCCl>[Br:1][CH2:2][C:3]([C:17]1[S:16][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[C:19]=2[CH:18]=1)=[O:4]
Reactant: Clc1cccc2sccc12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1cc2c(Cl)cccc2s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Bromoacetyl bromide (16.14 g) was added dropwise at 0° C. under nitrogen to a stirred mixture of anhydrous aluminium chloride (21.36 g) and dichloromethane (200 ml), then the mixture was stirred at 0° C. for 30 minutes. A solution of 4-chloro-benzo[b]thiophene (13.46 g; prepared in a manner similar to that described above) in dichloromethane (100 ml) was added dropwise, and the mixture was stirred at 0° C. for 2 hours then it was poured onto ice-water (500 ml). The product was extracted into dichloromethane (2×250 ml) and the combined extracts were washed with water (200 ml), saturated aqueous sodium hydrogencarbonate solution (2×200 ml) and saturated aqueous sodium chloride solution (200 ml), then dried (Na2SO4). The solvent was removed in vacuo to leave a brown oil, which was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (2.8 g) as a colourless solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4ccc(C)nc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), and 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998, 41, 4062), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62 mmol) was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried and the volatiles were removed by evaporation. The residue was triturated with minimal ether, collected by filtration and dried under vacuum to give 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (95 mg, 69%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[N:19]1)=O)(C)(C)C.[OH:36][CH2:37][CH2:38][O:39][C:40]1[CH:49]=[CH:48][C:43]([C:44](OC)=[O:45])=[CH:42][CH:41]=1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:20]2[NH:19][N:18]=[C:22]([NH:23][C:44](=[O:45])[C:43]3[CH:42]=[CH:41][C:40]([O:39][CH2:38][CH2:37][OH:36])=[CH:49][CH:48]=3)[CH:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COC(=O)c1ccc(OCCO)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(OCCO)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
A solution of NaHMDS in THF (1 M, 1.15 ml, 1.15 mmol, 2 eq) was added dropwise at ambient temperature to a mixture of tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.58 mmol, 1 eq) and methyl 4-(2-hydroxyethoxy)benzoate (136 mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred at ambient temperature for 1 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (29 mg, 12% yield); 1H NMR (399.902 MHz, DMSO) δ 2.89 (4H, s), 3.77-3.72 (8H, m), 4.07 (2H, t), 4.88 (1H, t), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.46 (1H, s), 7.01 (2H, d), 7.98 (2H, d), 10.46 (1H, br.s), 12.12 (1H, br.s). MS: m/z 412 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)[CH:25]=[CH:24][C:23]=1O)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:17]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: COc1ccc(C#CCCCCO)cc1
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCC#Cc1ccc(OC)cc1
Yield: 55 %

Procedure:
Following the procedure of Example 92B, 0.38 g of 6-(4-methoxyphenyl)-5-hexynyl alcohol were converted to the mesyl ester and reacted with 0.69 g of 5-[3-(ethoxycarbonyl)benzoyl]-2-hydroxybenzenepropanoic acid ethyl ester to provide the title product in 55% yield as an oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CN=C1>CO.CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[O:21])[CH2:14][S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[CH3:20]
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C(=O)CBr
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nnc(-c2ccccc2)o1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 5-phenyl-1,3,4-oxadiazole-2-thiol (178 mg, 1.0 mmol) and ethyl 3-bromopyruvate (0.150 mL, 1.19 mmol) in methanol (2 mL) and acetone (2 mL) was added imidazole (68 mg, 1.0 mmol). The resulted solution was shaken at 20° C. for 4 hour. After the removal of solvents under vacuum, the residue was triturated with ethyl ether. The ether phase was discarded. The residue was treated with sodium bicarbonate aqueous solution and ethyl ether. The ether phase was washed successively with sodium bicarbonate aqueous solution, water, and dried over magnesium sulfate. Evaporation to dryness under vacuum gave 209 mg (72% of yield) of the expected product, 2-oxo-3-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-propionic acid ethyl ester. Proton NMR showed the product was sufficiently pure to be used without further purification. 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.90-7.80 (m, 2H), 7.60-7.35 (m, 3H), 4.41 (q, J=7.1 Hz, 2H), 3.44 (br. s, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>COCCOC.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2,5-dibromopyridine (12.0 g) and thiophenol (5.46 mL) in DME (50 mL) was added sodium tert-butoxide (5.35 g) at room temperature and the mixture was stirred at 100° C. for 15 h. The reaction mixture was poured into brine, extracted with EtOAc, washed with brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 30:1) to give 5-bromo-2-(phenylsulfanyl)pyridine (13.69 g) as an oil.