Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Li])#[C:2][CH3:3].[O:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]>O1CCCC1>[OH:5][C:6]([C:1]#[C:2][CH3:3])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]
Reactant: CCCCC(=O)C/C=C/I
Reactant: [Li]C#CC
Solvent: C1CCOC1
Product: CC#CC(O)(C/C=C/I)CCCC
Reaction time: 0.5 h

Procedure:
To a stirred solution of propynyllithium at -25° is added a solution of 4-oxo-1-iodo-trans-1-octene in tetrahydrofuran. After the addition, the solution is stirred at -20° to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with toluene to provide the product as an oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][CH:33]([OH:36])[CH:34]=[CH2:35].O[C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=[O:42]>C1COCC1>[CH3:32][CH:33]([O:36][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=[O:42])[CH:34]=[CH2:35]
Reactant: C=CC(C)O
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)Oc1cccc(C=O)c1
Reaction time: 0.17 h

Procedure:
Added DEAD (0.964 mL, 6.142 mmole) dropwise to a solution of triphenylphosphine (0.1.611 g, 6.142 mmole), 3-buten-2-ol (Fluka, 0.423 mL, 4.91 mmole), and 3-hydroxy benzaldehyde (0.5 g, 4.09 mmole) in 10 mL dry THF, at rt, under Argon. After 10 min, the reaction was concentrated in vacuo and was purified on a 35 g Redisep column eluting with a gradient of 5%-30% EtOAc in hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: C1CCOC1
Product: OCc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 50.0 g (0.25 mols, Aldrich) of 3-bromobenzoic acid in 100 ml of dry tetrahydrofuran (THF) cooled to 0° is added slowly 100 ml (1.0M in THF, 100 mmols, Aldrich) of borane-tetrahydrofuran complex. The reaction is stirred at 0° for 1 hour then at room temperature for 18 hours. The reaction is quenched by dropwise addition of water then concentrated in vacuo to remove solvent. The residue is partitioned between diethyl ether and 1M aqueous HCl. The organic layer is separated, washed with 1M aqueous sodium hydroxide, brine, dried (magnesium sulfate) and concentrated in vacuo to afford title compound.
Reaction SMILES: [CH3:1][C@@:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:3](O)=[O:4].CN1CCOCC1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:41][NH2:42].O>CC1CCCO1>[CH3:1][C@@:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:3]([NH:42][O:41][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][O:35]1)=[O:4]
Reactant: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}butanoic acid (0.125 g, 0.321 mmol) in 2-methyltetrahydrofuran (20 mL) was added n-methyl morpholine (0.046 g, 0.449 mmol, 1.4 eq), followed by CDMT (0.068 g, 0.385 mmol, 1.2 eq). The reaction was allowed to stir for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.045 g, 0.385 mmol, 1.2 eq) was added, and the reaction mixture was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with 50%-100% ethyl acetate/heptane to yield (2R)-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (31 mg, 20% yield) as a colorless oil. LC-MS M−H 487.5.
Reaction SMILES: O.Cl.[CH2:3]([C:7]1([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6].[OH-].[Na+]>CC(C)=O>[CH2:3]([C:7]1([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1(N2CCCC2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC1(N2CCCC2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (10.0 ml) and 37% hydrochloric acid (14.0 ml) were added to a solution of 1-(8-butyl-1,4-dioxaspiro[4.5]dec-8-yl)pyrrolidine (2.70 g, 10.1 mmol) in acetone (100 ml) and the mixture was stirred at room temperature overnight. 4 M sodium hydroxide solution was then slowly added dropwise to the mixture until pH 10 was reached. The mixture was extracted with diethyl ether (4×40 ml) and the combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude produce (2.6 g) was purified by flash chromatography (260 g, 30×5.6 cm) with ethyl acetate/methanol (9:1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][N:11]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:3]=1[C:24]#[N:25].C(Cl)(Cl)(Cl)Cl.C(#N)C.N1C=CC=CC=1.N12CCCN=C1CCCCC2>>[Br:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:3]=1[C:24]#[N:25]
Reactant: COC(=O)C1CN=C(c2sc(Br)c(C#N)c2-c2ccc(Cl)cc2Cl)N1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cnc(-c2sc(Br)c(C#N)c2-c2ccc(Cl)cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a mixture of methyl 2-[5-bromo-4-cyano-3-(2,4-dichlorophenyl)-2-thienyl]-4,5-dihydro-1H-imidazole-5-carboxylate (0.341 g, 0.743 mmol), carbon tetrachloride (12.1 mL, 126 mmol), acetonitrile (18.3 mL, 351 mmol) and pyridine (12 mL, 150 mmol) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.442 mL, 2.96 mmol) slowly. The solution was stirred at room temperature for 16 hours. The mixture was evaporated, then the residue was diluted with dichloromethane and 0.5N aqueous HCl solution. The layers were separated, then the organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.226 g, 67%). LCMS: (FA) ES+, 458. 1H NMR (400 MHz, d4-Methanol) δ: 7.70-7.67 (m, 2H), 7.53-7.43 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][N:11]3[N:15]=[C:16]([NH2:18])[N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.CP(C)C.C1(C)C=CC=CC=1.[CH3:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]([N:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)[CH:39]=1.C(Cl)Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][N:11]3[N:15]=[C:16]([NH:18][CH:47]4[CH2:48][CH2:49][N:44]([C:40]5[CH:39]=[C:38]([CH3:37])[N:43]=[CH:42][N:41]=5)[CH2:45][CH2:46]4)[N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2n(n1)CCCN2c1ccc(F)c(F)c1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Agent: CP(C)C
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(Nc3nc4n(n3)CCCN4c3ccc(F)c(F)c3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3,4-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (41 mg, 163 μmol) in tetrahydrofurane (1 mL) was added under an atmosphere of nitrogen hexachloroethane (61.0 mg, 245 μmol), triethylamine (49.5 mg, 68.2 μL, 490 μmol) and a 1 M solution of trimethylphosphine in toluene (245 μL, 245 μmol). The suspension was stirred for 30 minutes at room temperature. 1-(6-Methylpyrimidin-4-yl)piperidin-4-one (see example 93b, 46.8 mg, 245 μmol) dissolved in tetrahydrofurane (0.5 mL) was added and the yellow suspension was heated to 150° C. for 30 minutes. A 1 M solution of borane tetrahydrofurane complex in methylene chloride (490 μL, 490 μmol) was added and the reaction was heated to 100° C. for one hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The title compound was obtained as a colorless solid (14 mg, 20%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent and subsequent purification with preparative HPCL. MS ISP (m/e): 427.3 (100) [(M+H)+], 176.3 (81).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].Cl>N1C=CC=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
4-Amino-4'-chlorobenzophenone (4 g.) was heated under reflux with a mixture of pyridine (15 ml.) and methanesulphonyl chloride (10 g.) for 30 mins. The mixture was then poured into a mixture of ice and hydrochloric acid and then filtered to give 4-chloro-4'-methylsulphonylaminobenzophenone m.p. 198°-200° C. A mixture of this product (2.4 g.) ethyl carbazate (2 g.) and a trace amount of pyridine hydrochloride in ethanol (50 ml.) was heated under reflux for 24 hours. The mixture was then cooled to 0° C. and filtered to give 4-chloro-4'-methylsulphonylaminobenzophenone ethoxycarbonyl hydrazone, m.p. 198°-200° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[O:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]=1[C:12]([C:14]1[CH:15]=[C:16]([Br:22])[C:17]([OH:21])=[C:18]([Br:20])[CH:19]=1)=[O:13].C1COCC1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>C([O-])(O)=O.[Na+]>[Br:22][C:16]1[CH:15]=[C:14]([C:12]([C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:3]=2[CH2:2][CH3:1])=[O:13])[CH:19]=[C:18]([Br:20])[C:17]=1[O:21][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1oc2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1oc2ccccc2c1C(=O)c1cc(Br)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(Br)c1
Reaction time: 18 h
Yield: 39.1 %

Procedure:
At ambient temperature, to a stirred solution of commercial benzbromarone (0.243 g, 0.574 mmol) in 0.5M aq. NaHCO3 :THF (8 mL; 1:1) was added portionwise 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After the addition was complete the reaction was stirred for 18 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After 2 h, the reaction was quenched with 2N HCl (25 mL), extracted with EtOAc and concentrated. The crude product was purified by preparative HPLC (C18, eluting with 75% CH3CN/H2O containing 0.1% TFA) and crystallized from EtOAc/hexane to give 0.14 g (39%) of the title compound as a white solid, mp 173° C.; 1H NMR (DMSO-d6) δ 1.25 (t, 3 H), 2.76 (q, 2 H), 7.30 (dt, 1 H), 7.36 (dt, 1 H), 7.44-7.49 (m, 3 H), 7.66 (d, 1 H), 8.03 (d, 1 H), 8.08 (s, 2 H). IR (KBr) 3400, 2950, 1680, 1650, 1400 and 1180 cm-1, mass spectrum (-ESI), m/z 621/623/625 (M-H). Anal. Calcd. for C24H16Br2O8S: C, 46.18; H, 2.58; N, 0.00. Found: C, 46.41; H, 2.64; N, 0.00.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:23])/[C:11](=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)/[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:24])[CH:3]=1>CC(O)=O.CCOC(C)=O.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:24])[CH:3]=1
Reactant: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)/C(=C/c2ccccn2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)C(Cc2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of (5E)-2-(4-bromo-2,6-dichloro-phenyl)-3-methoxy-5-(2-pyridylmethylene)cyclopent-2-en-1-one (235 mg, 0.55 mmol) in glacial AcOH (2.4 ml) at 0°C. was added zinc dust (126 mg, 1.94 mmol) portionwise over 10 minutes. The reaction was stirred at room temperature for 2 hours and then diluted with EtOAc (25 ml), filtered through Celite and washed through with further EtOAc (2×20 ml). The filtrate was evaporated to dryness under reduced pressure and then azeotroped with toluene and then MeOH to give the desired product (235 mg, 99%) as a brown gum. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (d, 1H), 7.60 (dd, 1H), 7.45 (2×s, 2×1H), 7.25 (d, 1H), 7.15 (dd, 1H), 3.80 (s, 3H), 3.45-3.35 (1H, m), 3.20-3.10 (m, 1H), 3.00-2.90 (1H, m), 2.90-2.85 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cncc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A suspension of N-(5-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (60 mg, 0.144 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3.MeOH in DCM to give N-(5-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (30 mg, 0.090 mmol, 62.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.66 (s, 1H); 13.09 (s, 1H); 9.84 (dd, J=7.82, 1.56 Hz, 1H); 8.63 (s, 1H); 8.46 (d, J=1.76 Hz, 1H); 8.41 (dd, J=4.69, 1.76 Hz, 1H); 8.20 (s, 1H); 7.95 (d, J=2.54 Hz, 1H); 7.10 (dd, J=7.82, 4.69 Hz, 1H); 3.87 (s, 3H); 2.89 (s, 3H). m/z (ESI, +ve ion) 334 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.O>[O:12]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11]
Reactant: COCCOCCOCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOCCOc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Chloride 603 (26 g, 0.14 mol, 1.3 equiv) and p-hydroxybenzaldehyde (13 g, 0.11 mol, 1 equiv) were dissolved in dry THF (40 mL). K2CO3 (15 g, 0.11 mol, 1 equiv) was added followed by 18-crown-6 (3.0 g, 11 mmol, 0.11 equiv) and KI (0.20 g, 1.2 mmol, 0.01 equiv). The reaction mixture was stirred at reflux for 48 h. The resulting mixture was cooled to room temperature, and water (200 mL) was added. The product was extracted with 3×350 mL portions of ethyl acetate and the combined organic layers were dried and concentrated. The oil was loaded onto a silica gel column and eluted with a 1:9 mixture of ethyl acetate/hexane, followed by a ratio of 1:4, 3:7, 4:1 of ethyl acetate/hexane and finally washed with ethyl acetate to afford 21 g (70%) of 604 as a clear oil. IR (cm−1): 1697 (s), 1165 (s). 1H NMR (400, CDCl3): δ 3.36 (s, 3), 3.54 (t, 2, J=4.6), 3.63–3.68 (m, 4), 3.72–3.75 (m, 2), 3.88 (t, 2, J=4.8), 4.20 (t, 2, J=4.8), 7.01 (d, 2, J=8.8), 9.87 (s, 1). 13C NMR (CDCl3): δ 58.86, 67.59, 69.29, 70.40, 70.47, 70.71, 71.73, 114.71, 129.84, 13.1.76, 163.69, 190.63. Calcd: [M+H]+ (C14H21O5) m/z=269.13889. Found FAB-HRMS: [M+H]+ m/z=269.134487. Anal. Calcd. for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.47; H, 7.74.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14]Br>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([CH:7]([NH2:8])[CH2:4][CH:5]([CH3:9])[CH3:6])[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCBr
Product: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Yield: 56.2 %

Procedure:
As described in article (Chinese Journal of Pharmaceuticals, 2001, 32(8): 337-339), p-chlorobenzyl cyanide was condensed with 1,3-dibromopropane, cycled to give cyclobutyl inter mediate, and then through Grignard reaction and reduction reaction to give title compound (56.2% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH:19]=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:28][C:26](=[NH:27])[CH2:25][O:24][CH2:23][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:29])([F:30])[F:13])[CH:17]=1)=[O:6]
Reactant: N=C(N)COCCc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1cccc(OC(F)(F)F)c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{1-imino-2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-ethyl}-nicotinamide as orange oil. MS: m/e=436.2 [M+H+].
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[NH2:10][C:11]1[S:12][C:13](Br)=[N:14][N:15]=1>O.C(O)C>[NH2:10][C:11]1[S:12][C:13]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:14][N:15]=1
Reactant: Nc1nnc(Br)s1
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nnc(Sc2ccccc2)s1
Temperature: 82 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
In a mixture of 20 ml of water and 30 ml of ethanol, 7.3 g of thiophenol and 4.5 g of potassium hydroxide were added. To this solution, 11.7 g of 2-amino-5-bromo-1,3,4-thiadiazole was added, and the mixture was heated to 82° C. and stirred for 2 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water and n-hexane respectively, dried under reduced pressure, and thus 10.8 g of 2-amino-5-phenylthio-1,3,4-thiadiazole was obtained. m.p. 202°~203° C. Yield 77%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[CH3:34][N:35]1[CH:39]=[CH:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[N:36]1.O>C1COCC1.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:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([C:39]4[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=4)[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)([CH3:30])([CH3:32])[CH3:31]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccn(C)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 53, 100 mg, 0.185 mmol), 1-methyl-3-(tributylstannyl)-1H-pyrazole (62.4 mg, 0.168 mmol, prepared according to Heterocycles, 1997, 45, 1463), and PdCl2(PPh3)2 (11.8 mg, 0.0168 mmol) in THF (1.0 mL) was refluxed overnight. After cooling to room temperature, water was added, the reaction mixture was extracted with EtOAc, and the organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 542.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.66 (1H, d), 7.59 (1H, s), 7.50 (1H, s), 7.38 (111, d), 7.18 (2H, d), 7.08-7.13 (2H, m), 6.97 (2H, d), 6.40 (1H, s), 4.60-5.00 (2H, br s), 3.97 (3H, s), 1.26 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Yield: 102.2 %

Procedure:
In methyl ethyl ketone (10 mL) were suspended the obtained 3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (209 mg, 0.50 mmol), ethyl 2-bromo-2-methylpropionate (489 mg, 2.50 mmol), and potassium carbonate (346 mg, 2.50 mmol). The suspension was refluxed for 40 hours. The suspension was then allowed to room temperature, filtered to remove insolubles, and washed with methyl ethyl ketone. The solvent was distilled off. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (7/1) to give the desired compound (272 mg) as colorless oil (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Zn+])=[CH:15][CH:14]=1.NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1N
Reactant: Fc1ccc(C[Zn+])cc1
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: N#Cc1cc(Cc2ccc(F)cc2)ccc1N

Procedure:
From 9 (488 mg, 2 mmol) and 4-fluorobenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method as 10a; pale-yellow powder (275 mg, 51%): mp 105-107° C.; 1H NMR (CDCl3) δ 3.82 (s, 2H, CH2), 4.32 (br, 2H, NH2), 6.68 (d, J=8.8 Hz, 1H, H-3), 6.96-7.00 (m, 2H, 3′- and 5′-H), 7.08-7.14 (m, 3H, H-4, H-2′, and H-6′), 7.17 (s, 1H, H-6).