Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.[OH-].[K+]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:21][O:22][CH3:23])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: COCCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
3-Chloro-4-hydroxybenzoic acid 0.5 hydrate (2.00 g, 11.6 mmol) was suspended in dichloromethane (50 mL), and the suspension was added with diisopropylethylamine (8.10 mL, 46.5 mmol) and chloromethyl methyl ether (1.80 mL, 23.7 mmol), under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was added with chloromethyl methyl ether (0.45 mL, 5.92 mmol) under ice-cooling, and stirred at room temperature for 1.5 hours. The reaction mixture was added with methanol (100 mL) and 4 mol/L aqueous potassium hydroxide solution (50 mL) and stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue was added with 4 mol/L hydrochloric acid and water, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-chloro-4-methoxymethoxybenzoic acid (2.39 g, yield 95%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=O)=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1.C(O)(C(F)(F)F)=O>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:48])=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.112 g, 0.445 mmol) in tetrahydrofuran (1.780 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.490 ml, 0.490 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate (Intermediate AAAAAA; 0.230 g, 0.445 mmol) in THF (1.5 mL) was added drop wise, and the reaction was stirred for two hours. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 12-g Redi-Sep Gold column with 0-50% EtOAc/Heptane. The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.48 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.97 (dd, J=1.8, 8.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 7.25 (dd, J=1.8, 8.1 Hz, 1H), 3.72 (s, 3H). m/z (ESI) 434.0 (M+H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Condensation of Z-Phe-OH (15.0 g.) and H-Trp-OCH3 (12.8 g.) by the mixed anhydride method using isobutyl chloroformate (6.52 ml.) and triethylamine (10.1 g.) in tetrahydrofuran for a few minutes at -20° C. and then for about 1 hr. at room temperature, isolation of the crude product by ethyl acetate extraction, and purification by crystallization from ether-hexane gave Z-Phe-Trp-OCH3 (21.5 g., 8670 yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]#[N:18])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][CH:7]=1.[Sn](Cl)Cl>C(O)C.O1CCCC1>[NH2:14][C:10]1[CH:9]=[C:8]([C:5]2[C:4]([C:17]#[N:18])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cc(F)ccc1-c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1-c1cccc(N)c1

Procedure:
4-Fluoro-3′-nitrobiphenyl-2-carbonitrile was reduced by treatment with tin(II) chloride in ethanol and tetrahydrofuran to give 3′-amino-4-fluorobiphenyl-2-carbonitrile as a brown solid: δH (360 MHz, CDCl3) 6.76 (1H, ddd, J 8, 2 and 2), 6.80 (1H, dd, J 2 and 2), 6.87 (1H, ddd, J 8, 1 and 1), 7.27 (1H, dd, J 8 and 8), 7.35 (1H, ddd, J 8, 8 and 3), 7.41-7.51 (2H, m).
Reaction SMILES: [Cl-].[CH2:2]([N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:24][CH2:25][N:26]1[C:32](=[O:33])[C:30](=[O:31])[N:29]([C:34]([NH:36][C@@H:37]([C:44]([NH:46][C@@H:47]2[C:50](=[O:51])[N:49]3[C@@H:52]([C:57]([O-:59])=[O:58])[C:53]([CH3:56])([CH3:55])[S:54][C@H:48]23)=[O:45])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:28][CH2:27]1.[Na+].C(Cl)(Cl)Cl>O>[CH2:2]([N+:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:24][CH2:25][N:26]1[C:32](=[O:33])[C:30](=[O:31])[N:29]([C:34]([NH:36][C@@H:37]([C:44]([NH:46][C@@H:47]2[C:50](=[O:51])[N:49]3[C@@H:52]([C:57]([OH:59])=[O:58])[C:53]([CH3:55])([CH3:56])[S:54][C@H:48]23)=[O:45])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:28][CH2:27]1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)[O-])c2ccccc2)C(=O)C1=O
Agent: CCCCCCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)O)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Yield: 58.66 %

Procedure:
Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium piperacillin (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature, and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and a soft orange solid was obtained in 58.66% yield. Melting point (hot plate apparatus)=30-40° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30].O>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CCCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 12 h

Procedure:
To a solution of 6 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine and 5.1 ml diisopropylethylamine in 500 ml dichloromethane was added 3.1 ml of butyryl chloride. This solution was stirred for 12 hours then poured onto 200 ml of water and extracted with 150 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and the solid chromatographed on 500 g silica gel with dichloromethane-methanol (95:5). The fractions containing the desired product were combined, concentrated in vacuo and the solid recrystallized from dichloromethane-hexane to give 5.58 g of white crystals, mp 195°-198° C.
Reaction SMILES: C([N:8]1[C:17]2=[CH:18][CH:19]=[CH:20][C:15]3=[C:16]2[N:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:21])[C:9]1=[O:22])C1C=CC=CC=1.OP(O)(O)=O.C1(O)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[NH:8]1[C:17]2=[CH:18][CH:19]=[CH:20][C:15]3=[C:16]2[N:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:21])[C:9]1=[O:22]
Reactant: O=C1CCCn2c(=O)n(Cc3ccccc3)c3cccc1c32
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: O=C1CCCn2c(=O)[nH]c3cccc1c32
Temperature: 150 °C
Yield: 48 %

Procedure:
A mixture of 29.2 g of the product of Step C, 292 g of o-phosphoric acid and 14.1 g of phenol were heated at 150° C. under an inert atmosphere for 2 hours, was cooled to about 35° C. and was poured into 1200 ml of iced water with stirring. 2 liters of methylene chloride were added to the mixture which was then made alkaline with sodium hydroxide. The mixture was filtered and the solids were washed with methylene chloride. The combined organic phases were washed, dried and evaporated to dryness under reduced pressure. The residue was crystallized and was chromatographed over silica gel. Elution with a 90-2-2 ethyl acetate-methanol-triethylamine mixture yielded 9.7 g of 5,6-dihydro-imidazo[4,5,l-j-k][1]benzazepin-2,7-[1H,4H]-dione melting at 235° C.
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2>>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH:13]=[CH:12]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CCC(CC)CBr
Product: CCC(CC)Cn1ccc2cc(Br)ccc21

Procedure:
The title compound was prepared from 1-bromo-2-ethylbutane (14.14 mL, 101 mmol) and 5-bromoindole (20 g, 101 mmol) in substantially the same manner, as described in Step 1 of Example 25. The product (17.78 g, 62%) was obtained as a colorless oil. Mass spectrum (ESI, [M+H]+) m/z 280. 1 HNMR (400 MHz, DMSO-d6): δ 7.71 (d, 1H, J=1.83 Hz), 7.43-7.39 (m, 2H), 7.21 (dd, 2H, J=8.72 and 1.99 Hz), 6.41 (d, 1H, J=2.90 Hz), 4.04 (d, 2H, J=7.48 Hz), 1.76 (hep, 1H), 1.21 (p, 4H), and 0.82 ppm (t, 6H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>O.C1(C)C=CC=CC=1.O1CCCC1>[CH3:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:13]1[O:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=2[N:12]=1
Reactant: Cc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a mixture of 0.38 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-methylisonicotinamide, 5 ml of tetrahydrofuran and 0.42 g of triphenylphosphine, 0.69 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature and stirred while heating at 60° C. After three hours, 5 ml of 10% aqueous solution of sodium hydroxide was added and stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.29 g of 2-(3-methylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 23”).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[S:12])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH:14]([CH3:18])[C:15](=O)[CH3:16].O=P(Cl)(Cl)Cl>CCO>[CH2:1]([O:3][C:4]([C:6]1[N:7]2[C:8]([S:12][C:14]([CH3:18])=[C:15]2[CH3:16])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc2sc(C)c(C)n12

Procedure:
A mixture of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (10.7 mmol) and 3-bromo-2-butanone (10.7 mmol) in EtOH (16 mL) is heated at reflux for 3 h. The solvents are removed in vacuo and POCl3 (161 mmol) is added. The mixture is stirred at reflux for 3 h, concentrated in vacuo and diluted with chloroform. Ice water is added and the mixture is neutralized by addition of Na2CO3. The layers are separated and the aq. layer is extracted with chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give a mixture of two regioisomers which are separated by FC (heptane/EtOAc 9/1 to EtOAc). 2,3,6-trimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester is obtained as minor isomer. LC-MS: tR=0.84 min; [M+H]+=239.0.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]([OH:14])[CH3:13])[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:14][CH:12]([CH:9]1[CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10]1)[CH3:13])(=[O:17])[CH3:16]
Reactant: CC(O)C1CCC(OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C)C1CCC(OC(C)(C)C)CC1
Temperature: 20 °C

Procedure:
A mixture of 200 g (1 mole) of 1-(p-tert.-butoxycyclohexyl)-ethan-1-ol and 306 g (3 moles) of acetic anhydride was refluxed for 30 minutes. 260 g of a mixture of acetic acid and excess acetic anhydride were distilled off in the course of 3 hours under atmospheric pressure, and the residual acetic anhydride was then removed under reduced pressure (20 mbar). The residue was cooled to 20° C., washed with water and aqueous bicarbonate solution and again with water and then fractionated to give 218 g of a fraction which distilled over at 90° C./0.1 mbar and had an interesting herbaceous fruity note.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH:2]=1.[ClH:20]>ClCCl.O1CCOCC1>[ClH:20].[NH:10]1[CH2:11][CH2:12][CH:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cncc(OC2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a cooled solution of tert-butyl 3-(pyridin-3-yloxy)pyrrolidine-1-carboxylate (600 mg, 2.27 mmol; which may be prepared as described in Step 1) in dichloromethane (15 mL) was added dropwise HCl 4N in dioxane (11.1 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (263 mg, 58%) as a yellow wax.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[C@@H:10]([CH3:22])[CH2:9]2)=[C:4]2[CH:23]=[N:24][CH:25]=[CH:26][C:3]=12.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:22][C@H:10]1[CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[C:3]3[CH:26]=[CH:25][N:24]=[CH:23][C:4]=23)[CH2:13][CH2:12][N:11]1[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)N1CCCCC1
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: [Na+]
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1

Procedure:
Using methods described in Example 1, and starting with (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 7 (150 mg, 400 μmol), Pd(PPh3)4 (23 mg, 20 μmol), 4-(trifluoromethyl)phenylboronic acid (106 mg, 560 μmol), and 2 M sodium carbonate (400 μl, 800 μmol), (S)-(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)(piperidin-1-yl)methanone 8 was obtained. MS 484.2 (calc'd) 485.2 (M+H, found).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:7]([O:17][CH2:18][CH2:19][O:20][CH3:21])[N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:16][C:13]1([F:15])[CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:12]1
Reactant: COCCOc1nc(C(=O)OC)ccc1N1CC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1nc(C(=O)O)ccc1N1CC(F)(F)C1
Yield: 83.3 %

Procedure:
A solution of 5-(3,3-difluoroazetidin-1-yl)-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (0.25 g, 6 mmol) in THF/H2O (30 mL) was stirred at room temperature for 3 h. After removal of the organic solvent, the aqueous phase was extracted with ethyl acetate (20 mL) and then acidified with 6 N hydrochloric acid to pH 2 to form a precipitate which was collected by filtration and dried under reduced pressure to give the target compound (0.24 g, 84%) as off-white solid which was used directly in the next step without further purification; MS (EI): m/e=289.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:15])[CH3:2].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:13][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([CH3:15])=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CCn1c(C)nc2cc(C(=O)O)ccc21
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCn1c(C)nc2cc(C(=O)OC)ccc21
Reaction time: 6 h

Procedure:
To a suspension of 1.1 g (5.4 mmol) of the title C compound, 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid in 25 mL of MeOH is added dropwise 0.7 g (5.9 mmol) of thionyl chloride and the resulting solution is stirred at 700 for 6 h, then at RT for 18 h. The solvent is removed under reduced pressure and 8% aqueous NaHCO3 solution is added to the residue. The mixture is extracted with EtOAc and the organic phase is dried over anhydrous Na2SO4. The organic solution is concentrated until the product precipitated. The solid is collected by filtration, washed with EtOH and MTBE to give 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a beige solid: mp=118-121° C.; IR (KBr) 3430, 1695 cm−1; 1H-NMR (CDCl3) δ 8.39 (s, 1H), 7.98 (dd, 1H), 7.32 (d, J=8.45, 1H), 4.19 (q, 2H), 3.94 (s, 3H), 2.64 (s, 3H), 1.43 (t, 3H); [M+1]+=219.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:22])[CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 3-bromopropylamine hydrobromide (2.91 g, 13.3 mmol) in 10 mL of CH2Cl2 was added 2.8 mL of triethylamine (20.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, followed by addition of diphenyl acetyl chloride (2.56 g, 11.1 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred for 40 minutes at room temperature and then diluted with 200 mL of CH2Cl2. The solution was washed with aqueous 0.5 N HCl (100 mL×3), water (50 mL), NaHCO3 (sat, 100 mL) and NaCl (sat), dried over MgSO4. Removal of solvent gave the crude product as a light yellow solid that was used in the next step without further purification (3.33 g, 91%): 1H NMR (400 MHz, CDCl3) δ 7.56–7.45 (m, 10H), 5.88–5.69 (br, 1H), 4.92 (s, 1H), 3.47–3.39 (m, 2H), 3.35 (t, 2H, J=6.4 Hz), 2.16–1.98 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][NH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)CCl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CNc1ccc(OCc2ccccc2)cc1

Procedure:
4-Benzyloxyaniline hydrochloride (70 g), methyl chloroacetate (49 ml) and sodium bicarbonate (75 g) in dry acetonitrile (200 ml) were heated at reflux for 6.5 h. Work up according to the method of Intermediate 8 gave a solid which was recrystallised from chloroform-hexane to give the title compound (55 g), m.p. 106°-107°.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]([NH2:41])=O)[CH2:35][CH2:34]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[C@H:33]1[CH2:34][CH2:35][C@H:36]([C:39]#[N:41])[CH2:37][CH2:38]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](C(N)=O)CC2)c2ncnn12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](C#N)CC2)c2ncnn12
Reaction time: 0.5 h

Procedure:
To a solution (10 mL) of trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexanecarboxamide (0.31 g) and pyridine (0.18 mL) in tetrahydrofuran was added trifluoroacetic acid anhydride (0.15 mL) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 60%).