Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:12].O>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(I)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
Crude 4-iodobenzoyl chloride (11.4 g, 42.7 mmol) in THF (75 mL), prepared above, was treated with ammonium hydroxide (5 mL) followed by water (40 mL) at ambient temperature. The reaction mixture was stirred for 3 hours and then partitioned between EtOAc (50 mL) and brine (50 mL). The phases were separated and the organic phase was washed with 10% aqueous NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate volume was reduced until a white solid precipitated from solution. The white solid was collected by filtration and washed with diethyl ether to provide the desired product (10.2 g, 41.4 mmol, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:18]=1[NH2:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:19][C:18]2[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=2[CH3:16])[N:12]=1)[CH3:2]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2c(C)cc(C)cc2C)n1
Yield: 44.1 %

Procedure:
A mixture of 5.3 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid ethyl ester, 2.7 g of 2,4,6-trimethylaniline and 2.1 g of sodium carbonate in 50 ml. of ethanol was heated in an autoclave to 200°C. for 5 hr. The reaction mixture was filtered and water was added to initiate precipitation. The precipitate was removed by filtration and recrystallized from 95% ethanol to afford 3.2 g of product, mp. 100-103°C.
Reaction SMILES: [C:1](/[C:4](/[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)([OH:3])=O.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[NH2:34]>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19](/[C:4](/[C:1](=[O:3])[NH:34][C:30]2[S:29][CH:33]=[CH:32][N:31]=2)=[CH:5]\[CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C(/C(=O)O)c2ccc(S(C)(=O)=O)cc2)CC1
Reactant: Nc1nccs1
Product: CC(C)(C)OC(=O)N1CCC(/C=C(/C(=O)Nc2nccs2)c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
(E)-tert-Butyl 4-[2-carboxy-2-(4-methanesulfonylphenyl)vinyl]piperidine-1-carboxylate (Preparation 35, 3.17 g, 7.7 mmol) was condensed with thiazol-2-ylamine (2.32 g, 23.2 mmol), employing the procedure described in EXAMPLE 65, to give (E)-tert-butyl 4-[2-(4-methanesulfonylphenyl)-2-(thiazol-2-ylcarbamoyl)vinyl]piperidine-1-carboxylate: m/z (ES+)=492.2 [M+H]+. TFA (20 mL) was added to a stirred solution of the abovementioned carbamate (1.40 g, 2.8 mmol) in CH2Cl2 (20 mL). After 2 h, the solution was concentrated in vacuo. The residue was dissolved in H2O, then the solution was washed with EtOAc. The aqueous layer was concentrated to furnish the trifluoroacetate salt of (E)-2-(4-methanesulfonylphenyl)-3-piperidin-4-yl-N-thiazol-2-ylacrylamide: m/z (ES+)=392.1 [M+H]+. A stirred solution of imidazole (102 mg, 1.5 mmol) in anhydrous DMF (1 mL) was treated with Me3SiCl (114 μL, 0.9 mmol). After 20 min, the above trifluoroacetate salt (150 mg, 0.3 mmol) was added. The mixture was stirred for 16 h, before being partitioned between CH2Cl2 and 1M HCl. The organic layer was dried (MgSO4), filtered, concentrated, and flash chromatographed (EtOAc-MeOH, 97:3 to 19:1). Recrystallisation (EtOAc) of the residue gave the title compound: RTA=3.05 min; m/z (ES+)=420.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Reactant: CCOC(=O)C(CCBr)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Temperature: 25 °C
Yield: 117.8 %

Procedure:
A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5.0 g, 18.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)-4-phenylbutyl bromide (5.79 g, 20.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 10.28 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 9:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 8.08 grams (93%) of a viscous yellow oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[C:67]1([C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH2:71][CH2:70][CH2:69][CH:68]=1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:74]4[CH:73]=[C:72]([C:67]5[CH2:71][CH2:70][CH2:69][CH:68]=5)[CH:77]=[CH:76][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2=CCCC2)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(C4=CCCC4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-cyclopent-1-enyl-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=442.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.C(N(CC)CC)C.[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][CH:39]=O)=[CH:35][CH:36]=2)[CH:31]=[CH:30][O:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[C:28](=[O:27])[O:29][CH:30]=[CH:31]3)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: O=CCc1ccc2c(=O)occc2c1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(=O)occc4c3)CC1=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (26 mg, 0.089 mmol) and triethylamine (12.1 mg, 0.12 mmol) was dissolved in dichloroethane (10 ml) then (1-Oxo-1H-isochromen-6-yl) acetaldehyde (15 mg, 0.080 mmol) followed by sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added. The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine then dried over Na2SO4, filtered and concentrated. The compound was purified by preparative TLC plate to yield the title product. 1H-NMR (500 MHz, CDCl3) δ ppm 8.27 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.32 (d, J=5.7 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.50 (d, J=5.8 Hz, 1H), 4.90 (b, 1H), 3.28-3.39 (m, 4H), 2.92-3.03 (m, 6H), 2.76-2.86 (m, 4H), 2.04 (b, 1H), 1.89-1.98 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:14]([Si](C)(C)C)=[N+:15]=[N-:16].CCCCCC>C(OCC)(=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:11])[NH:16][N:15]=[N:14]2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1[nH]nnn1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Yield: 78.3 %

Procedure:
To 4-trifluoromethylphenyl isocyanate (2.89 ml, 20.2 mmol) was added 5.36 ml of azidotrimethylsilane (39.9 mmol), and the mixture was stirred at 110° C. for twenty-four hours. After cooling, the mixture was subjected to column chromatography using silicagel (eluate; ethyl acetate:hexane=1:1 to 2:1 to ethyl acetate) to collect a desired fraction to be concentrated. The crystals obtained were recrystallized from ethyl acetate-hexane to give 3.64 g of 1-(4-trifluoromethylphenyl)-5(1H,4H)-tetrazolone (78%) as colorless needles.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]([OH:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OC=C)(=[O:35])[CH3:34]>>[C:33]([O:17][C@@H:15]([C@H:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:16])(=[O:35])[CH3:34]
Reactant: C=COC(C)=O
Reactant: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)[C@@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
47.2 g of (2RS,3SR)-3-(4-phenoxyphenyl)-5-phenylpentan-2-ol was dissolved in 470 ml of vinyl acetate, and 19.4 ml of triethylamine was added. Then, 4.7 g of immobilized lipase (Toyothium LIP) was added, followed by stirring at 30° C. for 2 days. The enzyme was filtered off and then, washed with ethyl acetate. The filtrate and the washing liquid were put together, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 23.8 g of (2R,3S)-2-acetoxy-3-(4-phenoxyphenyl)-5-phenylpentane and 22.2 g of the above identified compound, respectively, as colorless oily substances. Further, the absolute configuration of the above-identified compound was determined by Mosher method (J. Am. Chem. Soc., vol. 113, p. 4092 (1991)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[Br:15][C:16]1[C:17](=[O:21])[CH2:18][CH2:19][CH:20]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C1COCC1.O>[Br:15][C:16]1[C:17](=[O:21])[CH2:18][CH2:19][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=C1CCC=C1Br
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Li]CCCC
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(Br)C(=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a -78° C. solution of 4-bromothioanisole (35.1 g, 173 mmol) in THF (500 mL) was added nBuLi (1.6M in hexanes, 107.5 mL, 172 mmol). The solution was stirred for 45 min, then a solution of 2-bromo-2-cyclopenten-1-one (25.4 g, 158 mmol) in THF (150 mL) was added and the mixture was allowed to warm to 0° C. and was quenched with saturated aqueous NH4Cl. The majority of the solvent was removed in vacuo and the residue was suspended in water and extracted with two portions of EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. This material was dissolved in DMF (300 mL), cooled to 0° C. and treated with PDC (72.4 g, 192 mmol). The resulting mixture was warmed to r.t. and stirred for 2 h, then poured into H2O (1.2 L) and extracted with two 500 mL portions of EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a light brown solid which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[C:5]2[O:4][C:3]1=[O:24].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)[CH:10]=[C:5]2[O:4][C:3]1=[O:24]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cnc3c(c2)oc(=O)n3C)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c(=O)oc2cc(CCN3CCN(c4ccccc4)CC3)cnc21
Temperature: 25 °C

Procedure:
3-methyl-6-[2-(p-toluenesulfonyloxy)ethyl]oxazolo[4,5-b]pyridin-2(3H)-one of Preparation 15 (210 mg, 1.2 mmol) is dissolved in 1,4-dioxane (8 ml). N-phenylpiperazine (0.10 ml, 1.38 mmol) and triethylamine (0.18 ml, 1.3 mmol) are added in succession to the reaction mixture. Stirring is maintained at room temperature for 24 hours. After the solvent has been evaporated off under reduced pressure, the residue is taken up in water. Extraction is carried out with dichloromethane and the organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off. The title product is purified by chromatography on silica gel (eluant: dichloromethane/methanol: 95/5). The yield obtained is 91%. ##STR66##
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[CH:31](NN)([CH3:33])[CH3:32]>>[CH:31]([N:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[N:2]1)([CH3:33])[CH3:32]
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CC(C)NN
Product: CC(C)n1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting isopropyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.33 (bs, 2 H), 8.24 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1H), 7.86 (s, 1H) 7.83 (m, 1 H), 7.72 (m 2H), 7.58 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.15 (d, J=9.1 Hz, 2H) 7.04 (m, 2H), 5.43 (s, 2H), 4.31 (m, 1H), 1.43 (d, J=6.6 Hz), 6H); MS: (M+H m/z=421.2).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([O:16]C)=O)[N:13]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:26]([NH:29][C:14]([C:12]1[N:13]=[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:9][C:10](=[O:19])[C:11]=1[OH:18])=[O:16])([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Product: CC(C)NC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Yield: 54.5 %

Procedure:
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.10 g, 298 μmol) and isopropylamine (0.5 ml; 6.10 mmol) to provide the title compound as an off-white solid (0.059 g; 54%). LCMS: m/z=412 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].[CH3:15][O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20].C[O-].[Na+]>CO>[CH3:15][O:16][C:17]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([F:13])([F:12])[F:11])=[N:2][O:1][C:19]=1[NH2:20])=[O:21]
Reactant: ON=C(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2C(F)(F)F)noc1N
Yield: 85.1 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-2-(trifluoromethyl)benzimidoyl chloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.14 g, 41.74 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (8.13 g, 28.42 mmol, 85%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]=[CH2:17])[O:8][C:6]=2[CH:7]=1.[OH:18][CH2:19][C@@H:20]([N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH2:21][CH:22]([CH3:24])[CH3:23].C(P(C(C)(C)C)C1(C(C)C)CC(C(C)C)=CC(C(C)C)=C1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][CH:22]([CH3:24])[CH2:21][C@H:20]([N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH2:19][O:18][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]=[CH2:17])[O:8][C:6]=2[CH:7]=1
Reactant: C=CC1Oc2cc(Cl)ccc2-c2ccncc21
Reactant: CC(C)C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C(C)(C)C)C(C)(C)C)C1
Solvent: Cc1ccccc1
Product: C=CC1Oc2cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc2-c2ccncc21
Temperature: 80 °C
Yield: 80.4 %

Procedure:
To a stirred suspension of 8-chloro-5-vinyl-5H-chromeno[3,4-c]pyridine (0.2 g, 0.821 mmol), (S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (0.609 g, 2.462 mmol), 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (0.209 g, 0.492 mmol), and cesium carbonate (0.401 g, 1.231 mmol) in toluene (25 mL) was added palladium (II) acetate (0.055 g, 0.246 mmol). Nitrogen gas was bubbled through the mixture for 5 min, and then the reaction mixture was heated to 80° C. for 14 h. The reaction was diluted with ethyl acetate (25 mL) and filtered through celite. The filtrate was washed with water (1×20 mL) and brine (1×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (60% ethyl acetate in hexanes) to afford 2-((2S)-4-methyl-1-(5-vinyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dione (0.3 g, 0.660 mmol, 40% yield for three steps). LCMS (ESI) m/e 455.2 [(M+H)+, calcd for C28H27N2O4 455.2]; LC/MS retention time (Method C): tR=2.16 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1[CH:29]=[CH:28][C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:27])[C:24](O)=[O:25])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1>C(OCC)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:24](=[O:25])[C:23]([N:20]3[CH2:19][CH2:18][CH:17]([CH2:16][C:15]4[CH:14]=[CH:13][C:12]([F:11])=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)=[O:27])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]cnc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from (1H-benzimidazol-5yl) amine [Synth. Commun., 29, 2435. (1999)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid Example 1b) according to the method described in Example 1c. Melting Point: 104-110° C. (diethylether)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([O:9][Si](C)(C)C)[C:7]#N.C(Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)OC(C#N)c1nccs1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1nccs1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
To a solution of the product from Step 1 (0.4 g, 1.9 mmol) in degassed THF (4 mL) at −78° C. was added LHMDs. After stirring at −78° C. for 15 min, benzyl bromide (0.27 mL, 2.3 mmol) was added, and stirring was continued at −78° C. for 15 min, followed by 1 h at r.t. The reaction was then quenched by the addition of saturated NH4Cl solution, and the product was extracted with EtOAc. The organic layer was washed with H2O and brine, and was then dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (1:10 EtOAc:hexane) to give 0.16 g of the product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol), and sodium bicarbonate (52.3 g, 622 mmol) were dissolved/suspended in water (182 mL) and acetone (112 mL). The flask was cooled in an ice bath and a solution of benzoyl chloride (17.7 mL, 152 mmol) in acetone (56 mL) was added drop-wise over 1 hour. After 16 hours the acetone was removed on the rotovap. Water (400 mL) was added and the resulting mixture acidified using 6 M HCl to pH <2. The aqueous layer was washed with 200 mL CH2Cl2 three times. Aqueous sodium hydroxide (5M) was added to pH >12, and this solution was extracted three times with 200 mL of CH2Cl2. The combined organics were dried (MgSO4) and evaporated to give a thick yellow oil. MS (M+H)+=205.1
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.F[S:9]([C:12]1[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10]>CN(C=O)C>[CH3:19][O:18][C:15]1[N:14]=[N:13][C:12]([S:9]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cccc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To an ice-cold suspension of sodium hydride (1.86 mmol, 74 mg) in DMF (1 mL) was added a solution of pyrrole (1.86 mmol, 125 mg) in DMF (2 mL). To this was added 3-fluorosulfonyl-6-methoxypyridazine (1.55 mmol, 298 mg) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O (20 mL) and EtOAc (20 mL) and the EtOAc layer was collected, dried, filtered and evaporated to a residue. The residue was purified by silica gel chromatography (eluent:hexanes:EtOAc::9:1) to obtain 3-methoxy-6-(pyrrole-1-sulfonyl)-pyridazine (30%, 112 mg).