Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[N:4][N:3]=1.BrC1N=NN(C2CC2)N=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])=[O:21]>>[CH:8]1([CH2:7][N:6]2[C:2]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([CH:23]=3)[CH:20]=[O:21])=[N:3][N:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: Brc1nnnn1CC1CC1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: Brc1nnn(C2CC2)n1
Product: COc1ccc(-c2nnnn2CC2CC2)cc1C=O

Procedure:
From a mixture of 5bromo-1-cyclopropylmethyl-1H-tetrazole with 5bromo-2-cyclopropyl-2H-tetrazole (1.91 g) and 3-formyl-4-methoxy-phenyl-boronic acid (1.86 g) to give the title compound (657 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][C:5]1=[O:14])[CH3:2].[H-].[Na+].[CH3:18]I>>[CH2:1]([S:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:14])[CH3:2]
Reactant: CCSC1(C)C(=O)Nc2ccc(F)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCSC1(C)C(=O)N(C)c2ccc(F)cc21

Procedure:
11.3 g (0.05 mole) of 3-(ethylthio)-5-fluoro-3-methyl-1,3-dihydro-2(2H)-indolone are methylated as described under 2.2, starting with 2.6 g (0.055 mole) of 50% strength NaH and 3.7 ml of methyl iodide.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C1COCC1>[Cl:1][CH2:2][C:3]1[N:4]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Reaction time: 72 h
Yield: 67.7 %

Procedure:
To a stirred solution of 2-chloromethylbenzimidazole (1.89 g, 11.4 mmol) in dry THF (57 mL) was added N,N-diisopropylethylamine (3.00 mL, 17.2 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.90 mL, 10.8 mmol) both via syringe under nitrogen at room temperature. The mixture was stirred for 3 days at which time the solvent was removed in vacuo. The residue was taken up in CH2Cl2 (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. Purification by flash chromatography (silica gel, 100:2:1 CH2Cl2-methanol-ammonium hydroxide) provided 2.17 g (65%) of the title compound as a yellow oil, which solidified on standing. 1H NMR (CDCl3) δ−0.06 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 3.57 (t, 2H, J=7.5 Hz), 4.91 (s, 2H), 5.65 (s,−2H); 7.31-7.36 (m, 2H), 7.50 (d, 1H, J=7.5 Hz), 7.78 (d, 1H, J=7.5 Hz).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C@H:15]2[CH2:22][CH2:21][C:18]3([CH2:20][CH2:19]3)[O:17][CH2:16]2)(=O)=O)=CC=1.[NH2:31][CH3:32]>C(O)C>[CH2:20]1[C:18]2([CH2:21][CH2:22][C@H:15]([CH2:14][C@H:13]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][NH:31][CH3:32])[CH2:16][O:17]2)[CH2:19]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCC3(CC3)OC2)NC(=O)OC(C)(C)C)cc1
Solvent: CCO
Product: CNC[C@H](C[C@H]1CCC2(CC2)OC1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
The (S)-2-(tert-butoxycarbonylamino)-3-((R)-4-oxaspiro[2.5]oct-6-yl)propyl 4-methylbenzenesulfonate was dissolved in 100 mL of 33% NH2Me in ethanol. The mixture was heated to 50° C. for 3 hr. After this time LC/MS analysis shows formation of the desired amine. The solution was evaporated and the residue taken up in EtOAc, washed with 10% K2CO3, brine, dried over Na2SO4, filtered and evaporated. The tert-butyl (S)-1-((R)-4-oxaspiro[2.5]oct-6-yl)-3-(methylamino)propan-2-ylcarbamate was used directly in the next step with no further purification. MS ESI +ve m/z 301 (M+1).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]([NH:17][NH2:18])=[O:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[K+]>CO.O>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:15]3[O:16][C:2]([NH2:1])=[N:18][N:17]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: N#CBr
Reactant: COc1ccc(C2(C(=O)NN)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2(c3nnc(N)o3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Cyanogen bromide (0.424 g, 4.0 mmol) was added to an ice-cooled slurry of 1-(4-methoxyphenyl)cyclopropanecarbohydrazide (0.750 g, 3.64 mmol) and potassium bicarbonate (0.50 g, 5.0 mmol) in methanol (8 mL). The mixture was stirred at 0° C. for 1 h. the ice bath was allowed to warm slowly and stirred at RT for overnight. The reaction mixture was diluted with water (10 mL), stirred for 1 h. The precipitate was collected by filtration and washed with water, and dried on high vacuum to afford the desired product (600 mg, 71.3%). Analytical LCMS: (M+H)+=232.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:34]([CH3:42])[CH2:35][CH:36]([CH3:41])[CH2:37][CH2:38][CH:39]=[CH2:40])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][CH2:29][CH3:30])=[CH:20][N:19]=2)[CH2:14][C@H:13]1[C:31](O)=[O:32])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:77][C@:78]1([C:83]([NH:85][S:86]([CH:89]2[CH2:91][CH2:90]2)(=[O:88])=[O:87])=[O:84])[CH2:80][C@H:79]1[CH:81]=[CH2:82]>ClCCl>[CH:89]1([S:86]([NH:85][C:83]([C@@:78]2([NH:77][C:31]([C@@H:13]3[CH2:14][C@@H:15]([O:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([O:28][CH2:29][CH3:30])=[CH:20][N:19]=4)[CH2:16][N:12]3[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@H:34]([CH3:42])[CH2:35][CH:36]([CH3:41])[CH2:37][CH2:38][CH:39]=[CH2:40])=[O:32])[CH2:80][C@H:79]2[CH:81]=[CH2:82])=[O:84])(=[O:88])=[O:87])[CH2:91][CH2:90]1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (600 mg, 1.0 mmole) in dichloromethane (10 mL) was added DIPEA (0.87 mL, 5 mmole), HATU (380 mg, 1.0 mmole) followed by (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (prepared according to the procedure described in WO 03/099274) (457 mg, 1.1 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired product tert-butyl ((3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (500 mg, 61%) as off-white solid. MS: MS m/z 797.2 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:31]=[C:30]([C:32]([NH:34][NH2:35])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:35][NH:34][C:32]([C:30]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([Cl:21])[CH:31]=3)=[O:33])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl
Temperature: 0 °C
Yield: 85.2 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.568 mmol, 154.8 mg) synthesized in Synthetic Example 3, methyl 2-chloro-4-hydrazinocarbonylbenzoate (0.568 mmol, 130.0 mg) synthesized in Reference Synthetic Example 41 and p-tosylic acid monohydride (30 mol %, 29.4 mg) were dissolved in isopropyl alcohol (15 mL) and stirred under heating with reflux for 8 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a white solid (233.7 mg, yield 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CO.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH2:11][O:10][CH3:9])[CH:3]=1
Reactant: COCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: COCCOc1cccc(Br)c1
Yield: 69.2 %

Procedure:
To a solution of 3-bromophenol (0.865 g, 5 mmol) in MeOH (1.5 ml) was added 2-bromoethyl methyl ether (0.56 ml, 6 mmol) followed by K2CO3 (0.68 g, 5 mmol). The mixture was heated using microwave irradiation in a CEM discover microwave synthesizer (50 W) at 100° C. until the reaction was complete. The reaction was diluted with ether and filtered to remove solid which was washed with further ether. Filtrate concentrated under reduced pressure to give (0.8 g) of product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2[C:4]([N:13]=1)=[N:5][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:7][CH:8]=2)[CH3:15]
Reactant: CNc1ccc(C(F)(F)F)nc1N
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2nc(C(F)(F)F)ccc2n1C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of N3-methyl-6-trifluoromethylpyridin-2,3-diamine (0.38 g), 2-ethylsulfanylbenzoic acid (0.40 g), WSC (0.42 g), and pyridine (3 ml) was stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, tripotassium phosphate (1.06 g) and 1-propanol (4 ml) were added, and stirred under reflux for 4 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 166).
Reaction SMILES: [CH3:1][C:2]1O[CH:4]=[CH:5][C:6](=[O:25])[C:7]=1[O:8][CH2:9][C@:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][NH2:30]>C(O)C>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][N:30]1[CH:4]=[CH:5][C:6](=[O:25])[C:7]([O:8][CH2:9][C@:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([NH2:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[CH3:1]
Reactant: NCc1c(F)cccc1F
Reactant: Cc1occc(=O)c1OC[C@@](N)(C(=O)OC(C)(C)C)c1ccccc1
Solvent: CCO
Product: Cc1c(OC[C@@](N)(C(=O)OC(C)(C)C)c2ccccc2)c(=O)ccn1Cc1c(F)cccc1F
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Crude 2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-4H-pyran-4-one (1.00 g, ˜2.90 mmol), 2,6-difluorobenzyl amine (700 μL, 5.8 mmol) and ethanol (3 mL) were combined and heated to 120° C. in a pressure vessel. After 16 h, the volatiles were removed in vacuo and the residue purified by column chromatography, eluting with EtOAc. The product was isolated as a white foam (204 mg, 0.43 mmol, 15%, assuming pure starting material). 1H NMR (CDCl3-300 MHz) δ 7.42-7.19 (m, 7H); 6.98 (t, J=8.1 Hz, 2H); 6.43 (d, J=7.8 Hz, 1H); 5.06 (s, 2H); 4.87-4.83 (m, 1H); 4.06 (dd, J1=9.9 Hz, J2=4.2 Hz, 1H); 3.93 (dd, J=9.9 Hz, J2=6.8 Hz, 1H); 2.34 (s, 3H); 1.42 (s, 9H); LRMS m/z 471.1 (M++1), 371.0 (M+−boc+1).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]1)[CH2:6]2.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[OH:1][C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:11]1)[CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CC3CCC(C2)C3=O)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CC3CCC(C2)C3(O)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the ketone obtained in Step B (65 mg, 0.21 mmol) in THF (2 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (0.25 mL). After being stirred at −78° C. for 3 hours, the reaction was quenched with aqueous ammonium chloride. The resulting solution was extracted with EtOAc 3 times. The combined EtOAc layers were dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 5%, 10% and 50% MeOH/CH2Cl2 provided 27 mg of the title compound as a mixture of two isomers (7:3). MS calculated (M+H)+ 387, found 387.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13])[N:8]=[C:7](/[CH:23]=[N:24]/O)[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])([F:14])[F:13])[N:8]=[C:7]([C:23]#[N:24])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(/C=N/O)ccc2cc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C#N)ccc2cc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethyl [(6-bromo-2-[(E)-(hydroxyimino)methyl]quinolin-7-yl)(difluoro)methyl]phosphonate (520 mg, 1.189 mmol) in acetonitrile (30 mL) at room temperature were added triphenylphosphine (1.248 g, 4.76 mmol) and carbon tetrachloride (230 μL, 2.383 mmol). The reaction mixture was stirred at 100° C. for 1 hour. It was concentrated to dryness in vacuo, pre-adsorbed in silica gel for flash chromatography eluting with ethyl acetate in toluene (20% to 30%) to afford diethyl [(6-bromo-2-cyanoquinolin-7-yl)(difluoro)methyl]phosphonate.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]1=[O:11]>CO.CC(O)=O.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1cc([N+](=O)[O-])ccc1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc(N)ccc1=O

Procedure:
A solution of compound 50B (200 mg, 1.298 mmol) and 10% Pd/C (˜5 mg) in MeOH and AcOH was stirred under H2 at 1 atmosphere for 30 minutes. The reaction solution was filtered through a pad of celite eluting with MeOH. The MeOH was removed under reduced pressure to give compound 50C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of ice-cooled methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred for 2 hours with ice cooling. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=17:3) to give the title compound (0.62 g, yield 59%) as powders.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([SH:40])[CH:36]=[CH:37][C:38]=1[Cl:39]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:40][C:35]2[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN=C(O)c1cc([N+](=O)[O-])cc(Sc2ccc(Cl)c(Cl)c2)c1C(=O)O
Reaction time: 8 h

Procedure:
20.09 g (80 mmols) of 3,5-dinitrophthalic acid N-methylimide [prepared according to Example 2] are initially introduced into 300 ml of ethyl acetate and treated with 33.6 g (243 mmols) of ground, anhydrous potassium carbonate, and 15.04 g (84 mmols) of 3,4-dichlorothiophenol are then added dropwise at 25° C. After the addition of 100 ml of tetrahydrofuran, the mixture is stirred overnight and evaporated to dryness and the residue is taken up in a mixture of methylene chloride and dilute hydrochloric acid. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from methylene chloride/n-pentane, 25.74 g (84% of theory) of the title imide, with a melting point of 167°-8° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:8][N:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH:29](=O)CCC>>[CH2:1]([C:2]1[N:6]2[C:7]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:8][N:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1)[CH3:29]
Reactant: CCCC=O
Reactant: Cc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n12
Product: CCc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n12

Procedure:
This compound may be prepared using the methods described for Compound 131, using butanal in step 1. LCMS: Rt=0.94 min (100%), m/z (ESI) 390 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH3:19][N:20]([CH3:24])[C:21]([N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:22]
Reactant: CN(C)CCNc1nccs1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)N(C)C)c1nccs1

Procedure:
Following the procedure of Example 1C using 18.2 g. (0.1065 moles) of N,N-dimethyl-N'-(2-thiazolyl)-1,2-ethane diamine, 12.1 g. (0.120 moles) of triethylamine, 12.5 g. (0.116 moles) of dimethylcarbamoyl chloride and 135 ml. of dry benzene, there is obtained 20.1 g. of N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-thiazolyl) urea as an oil which is distilled at 108°-110° C., at 0.02 mm. of Hg.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]4[CH:54]=[C:55]([O:63][CH3:64])[C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 805.1 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:12]O[C:10]=1[C:21]([O:23]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[NH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:12][N:31]2[CH2:32][CH2:33][NH:34][C:21](=[O:23])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1occ(-c2nccs2)c(=O)c1OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1NCCn2cc(-c3nccs3)c(=O)c(OCc3ccccc3)c21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Methyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47 g) was suspended in ethanol (15 ml)-dioxane (15 ml), and tert-butyl (2-aminoethyl)carbamate (0.816 ml) was added. After stirring at 70° C. for 1.5 hr, the solvent was evaporated and 4N hydrochloric acid/dioxane solution (70 ml) and chloroform (10 ml) were added to the residue. After stirring at room temperature for 2 hr, the reaction mixture was concentration under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (20 ml) and methanol (50 ml) were added to the residue and the mixture was stirred for 2 hr. The solvent was evaporated and the obtained solid was collected by filtration and washed thoroughly with water to give 9-benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (1.07 g)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1cccc(C(=O)O)c1
Solvent: ClCCl
Product: CC(C)Oc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 3-isopropoxybenzoic acid (50 mmol) and dichloromethane (100 mL). Cool in an ice bath. Add in dropwise fashion, oxalyl chloride (55 mmol). Allow the reaction mixture to warm to ambient temperature. After 2 h, concentrate in vacuo to obtain a residue. Use the title compound without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:19])[CH3:18]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:19])[CH3:18])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1Br)CC=C2CCN
Agent: Cl
Product: COc1cc2c(cc1Br)CC=C2CCNC(C)=O

Procedure:
Starting with 2-(6-bromo-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and acetyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 83%).