Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.[C:18]1(C)[CH:23]=CC(S(OCCC#C)(=O)=O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:20][CH2:19][C:18]#[CH:23])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2)cc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCCC1c1ccc(/C=C/C(=O)OC)cc1
Temperature: 65 °C
Yield: 63 %

Procedure:
A mixture of (E)-3-(4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (5.52 g, 20.6 mmol), 3-butynyl p-toluenesulfonate (4.55 mL, 24.7 mmol) and potassium carbonate (5.98 g, 43.3 mmol) in acetonitrile (15 mL) was heated at 65° C. for 9 h. After cooled to room temperature, the reaction mixture was filtered, concentrated, and purified via silica gel column chromatography, and the residue was recrystallized from heptane to provide (E)-3-[4-(1-but-3-ynyl-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (3.68 g, 63% yield). LCMS (m/z): 284.2 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([N+:20]([O-:22])=[O:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].O>COCCO.CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([N+:20]([O-:22])=[O:21])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c([N+](=O)[O-])cc2c1=O
Reactant: C=CC(=O)OC
Solvent: COCCO
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCN1CCN(c2cc3c(cc2[N+](=O)[O-])c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 75.1 %

Procedure:
537 mg (0.0015) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in a mixture of 7.5 ml of glycol monomethyl ether and 3 ml of dimethylsulphoxide are heated under reflux with 2 g of methyl acrylate for 8 hours. 10 ml of water are added to the solution and the precipitate is filtered off with suction, washed with methanol and dried. 0.5 g of 1-cyclopropyl-1,4-dihydro-7-[4-(2-methoxycarbonylethyl)-1-piperazinyl]-6-nitro-4-oxo-3-quinolinecarboxylic acid of decomposition point 208° to 211° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:36][C:37]([CH3:42])([CH3:41])[C@@H:38]([NH2:40])[CH3:39].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:39][C@H:38]([NH:40][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[C:37]([CH3:42])([CH3:41])[CH3:36]
Reactant: C[C@H](N)C(C)(C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A round-bottomed flask was charged with 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.40 mmol), HOBT (68 mg, 0.44 mmol) and EDC (85 mg, 0.44 mmol). DMF (1.8 ml) was added followed by (S)-3,3-dimethylbutan-2-amine (0.10 ml, 0.73 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 97 mg (50%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light brown oil.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5][C:6]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>Cl>[CH3:1][C:2]1[NH:5][C:6]2[C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]=1
Reactant: CC(=O)O
Reactant: Nc1cccc(C(=O)O)c1N
Agent: Cl
Product: Cc1nc2cccc(C(=O)O)c2[nH]1
Yield: 72 %

Procedure:
Acetic acid (0.23 ml) was added to a solution of 2,3-diaminobenzoic acid (200 mg, 1.32 mmol) in hydrochloric acid (4M, 3.2 ml) and the mixture was refluxed for 1 hour. Solvents were evaporated and the residual solid was redissolved in boiling methanol (5 ml) and decolorised with activated charcoal. Removal of the solvent furnished 2-methylbenzimidazole-4-carboxylic acid as an amorphous white solid (167.5 mg, 72%); δH (d6 -DMSO) 2.9 (3H, s, imidazole-2-CH3), 7.6-7.8 (1H, t, Ar-5H) 8.1 (2H, d, Ar-4/6H); m/z (EI 176 (M+), 158, 130.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([N:2]1[CH2:3][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:12]=2)=[O:10])[CH3:7])[CH2:5]1)(=[O:49])=[O:48]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-azetidin-3-yl-ethyl)-amide hydrochloride (65 mg, 0.11 mmol) in CH2Cl2 (2 mL) at 0° C. was added triethylamine (47 μL, 0.33 mmol) followed by methanesulfonyl chloride (10 μL, 0.12 mmol). The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 35 mg (50%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide as a pale yellow solid.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]2)=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]1
Reactant: Cc1cncn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cncn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.33 h
Yield: 30 %

Procedure:
5-Benzyloxycarbonylamino-2-(5-methyl-imidazol-1-yl)fluorobenzene (3.2 g, 9.85 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6 M in isohexane, 6.81 ml). After stirring for 20 minutes at −70°, (R)-glycidylbutyrate (1.57 g, 10.09 mmol) was added at −70°. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated MeOH (10 ml), stirred 15 minutes, then poured into aqueous sodium bicarbonate (5%, 100 ml) and extracted with EtOAc (3×40 ml). The combined extracts were washed with brine (20 ml), dried (magnesium sulfate) and evaporated. and the residue purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated, to give the desired product (0.86 g). MS (ESP): 292 (MH+) for C14H14FN3O3.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:35](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O>C(Cl)(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[O:32][CH3:35])=[O:11])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 4 h

Procedure:
(ai) A suspension of 4.85 g of 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 25 ml of carbon tetrachloride and 27 ml of water is treated, at 20°, whilst stirring vigorously, successively with 3.0 g of potassium bicarbonate, 3.8 ml of dimethyl sulphate and 1.93 g of tetrabutylammonium bromide. The mixture is stirred vigorously for 4 hours at 20°. After diluting with 50 ml of water, the mixture is extracted with twice 50 ml of methylene chloride. 7β-Phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained by evaporating the extracts, previously dried over sulphate, and crystallising the residue from methylene chloride/diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1.Cl.[CH2:30]([O:32][NH2:33])[CH3:31].Cl>N1C=CC=CC=1>[CH2:30]([O:32][N:33]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:21][C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:19][C:18]=2[Cl:28])=[CH:10][CH:11]=1)[CH3:16])[CH3:31]
Reactant: CCON
Reactant: CC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.4 %

Procedure:
To a mixture of 0.31 g of 4′-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)acetophenone (which had been produced in Intermediate Production Example 2 as described below) and 10 ml of pyridine was added 0.07 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.33 g (yield, 99%) of 4′-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)acetophenone O-ethyloxime, nD24.5 1.5948.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[N:19][CH:20]=1.C(N)(N)=O.OO.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[N+:19]([O-:4])[CH:20]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
With cooling with ice, trifluoroacetic anhydride (11.9 mL, 84.2 mmol) was added to a chloroform (50 mL) solution of 5-bromo-2-chloropyridine (8.1 g, 42.1 mmol) and percarbamide (8.3 g, 88.4 mmol), and stirred at room temperature for 1 hour. Sodium thiosulfate water was added to the reaction mixture, then stirred at room temperature for 40 minutes, and extracted twice with chloroform. The organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting solid was taken out through filtration, washed with diethyl ether and dried to obtain the entitled compound (6.85 g, 78%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH:6]([CH2:17][CH3:18])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C1C=CC=CC=1>[CH:1]1([CH:6]([CH2:17][CH3:18])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(C(=O)c1ccc(OC)cc1)C1CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCC(C(=O)c1ccc(O)cc1)C1CCCC1

Procedure:
The mixture of 4.9 g (0.02 mol) of α-cyclopentyl-p-methoxy butyrophenone, 8.0 g (0.06 mol) of aluminium trichloride and 60 ml of benzene was refluxed for 3 hours. Dilute hydrochloric acid was added, the layers separated and the organic layer washed with water. The product was extracted with 2M sodium hydroxide. The alkaline solution was made acidic. The product was extracted with methylene chloride, dried and the solvent evaporated. The residue 4.1 g (0.018 mol, 88%) was crystallized from petroleum ether. Mp. 75°-78° C.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:34])([CH3:33])[CH2:31][OH:32])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>C1COCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:34])([CH3:33])[CH2:31][O:32][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:26][N:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CO)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)(COS(C)(=O)=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Temperature: 0 °C
Reaction time: 96 h
Yield: 99.9 %

Procedure:
2-[4-(4-Benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propane-1,2-diol (100 mg, 0.219 mmol) is combined with THF (1.5 mL). The reaction is chilled to 0° C. and triethylamine (95 μL, 0.329 mmol) is added followed by mesyl chloride (100 μL, 0.2 M in THF, 0.263 mmol). The reaction is allowed to warm to room temperature and stir for 96 h. Reaction is quenched with saturated ammonium chloride solution (0.5 mL), diluted with additional water and extracted with EtOAc. Wash combined organics with brine. Concentrate organics in vacuo to afford the title compound (117 mg, 99%).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: ClCCN1CCOCC1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: Cl
Product: CCCCN(CCCC)C(=O)c1cn(CCN2CCOCC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 69.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (280 mg, 0.57 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (106 mg, 0.57 mmol) were converted to the title compound (240 mg, 70%). 1H NMR (CDCl3) δ 8.68 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.0, 1.6 Hz, 1H), 7.62 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.36-7.32 (m, 3H), 7.25-7.23 (m, 2H), 5.14 (s, 2H), 3.97 (s, 3H), 3.92 (br s, 2H), 3.60-3.54 (m, 6H), 3.45 (br s, 2H), 2.37 (t, J=6.4 Hz, 2H), 2.20-2.18 (m, 4H), 1.63-1.56 (m, 4H), 1.38-1.22 (m, 4H), 0.95-0.82 (m, 6H); MS(ESI+) m/z 605.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[S:9][C:10]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:11][C:7]=2[CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[S:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2sc(C(=O)OC(C)(C)C)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2sc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of benzo[b]thiophene-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester (3.018 g, 10.32 mmol) and TFA (20 mL) in CH2Cl2 (50 mL) was allowed to stir at rt for four days. The reaction mixture was concentrated and dried under high vacuum to give benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester as a pale solid. MS (EI): cal'd 237.0 (MH+), exp 237.1 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=2[Cl:24])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=2[Cl:24])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Fc1ccc(F)c(Cc2cc(Cl)ncn2)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2c(F)ccc(F)c2Cl)ncn1
Temperature: 25 °C
Yield: 98 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.06 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-chloro-3,6-difluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(2-chloro-3,6-difluorobenzyl)pyrimidine (the present compound (130)).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CCl
Reactant: Oc1ccc(Cn2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cn2cccn2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 60 g of 4-(1-pyrazolyl)methylphenol, 54.9 g of ethyl chloroacetate, 95.1 g of potassium carbonate, and 500 ml of anhydrous dimethylformamide was heated at 50° C. under stirring for 5 hours, followed by cooling to room temperature. The reaction mixture was poured into 1 liter of water, which was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with water, saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 4-(1-pyrazolyl)methylphenoxyacetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]CC)=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Yield: 87.4 %

Procedure:
Ethyl 5-(4-chlorobenzoyl)pyrrole-3-carboxylate (0.7 g.) was combined with 20 ml. of methanol and 15 ml. of 1 N sodium hydroxide and boiled in an open flask for 1 hour. Most of the methanol evaporated. The mixture was diluted to 40 ml. with water, treated with activated charcoal, and acidified to yield 5-(4-chlorobenzoyl)-pyrrole-3-carboxylic acid [550 mg., m.p. 278°-280° C. (dec)]. Recrystallization from 1:1 methanol-acetone gave two crops of purified product [385 mg., m.p. 280°-282° C. (dec.)].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[O:4].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:40][C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([C:36]([F:35])([F:45])[F:46])[CH:38]=1)=[O:4]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CNC(C(=O)OC)C4)cc3)nc2n(CCC)c1=O
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)OC)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-pyrrolidine-2-carboxylic acid methyl ester (50 mg, 0.106 mmol) and TEA (32 mg, 0.319 mmol) in DCM (5 ml), 3-trifluoro methyl benzyl bromide (30 mg, 0.127 mmol) was added at 0° C. Reaction mixture was stirred at room temperature for 4 hr. Water was added into it and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to offer 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid methyl ester as an off white solid (25 mg, 37%).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[I-].[Na+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=1>C(O)(C)C>[I:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCCCN
Reactant: BrCCOc1ccc(I)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of dodecylamine (30 g, 162 mmol), diisopropylethylamine (22 ml, 128 mmol), sodium iodide (1.3 g, 8.5 mmol), 1-[2-bromoethoxy]-4-iodobenzene (13.9 g, 42.5 mmol) and isopropanol (250 ml) was stirred and refluxed for 24 h. After cooling to r.t., the mixture was filtered, washed with dichloromethane and concentrated in vacuo . The residue was chromatographed on silica gel (dichloromethane/methanol 50:1 to 20:1) to afford the title compound (15 g, 82%) as a white solid.