Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:69][O:70][C:71](=[O:89])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH2:53][O:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[C:57](=[O:68])[CH:58]=[C:59]([C:65]([OH:67])=[O:66])[O:60]2)[CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[C:41](=[O:52])[CH:42]=[C:43]([C:49]([OH:51])=[O:50])[O:44]2)=[O:34])=[O:26])[CH:22]([CH3:24])[CH3:23])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C>[NH2:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:69][O:70][C:71](=[O:89])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[C:41](=[O:52])[CH:42]=[C:43]([C:49]([OH:51])=[O:50])[O:44]2)[CH2:53][O:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[C:57](=[O:68])[CH:58]=[C:59]([C:65]([OH:67])=[O:66])[O:60]2)=[O:34])=[O:26])[CH:22]([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC(COc1cccc2oc(C(=O)O)cc(=O)c12)COc1cccc2oc(C(=O)O)cc(=O)c12)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC(COc1cccc2oc(C(=O)O)cc(=O)c12)COc1cccc2oc(C(=O)O)cc(=O)c12)COC(=O)[C@@H](N)C(C)C
Reaction time: 2 h

Procedure:
Dibenzyl ester of 2-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane (238 mg, (0.17 mmol) was dissolved in ethyl acetate (1.5 ml). To the solution was added 80% acetic acid (10 ml). After two hr, the solution was evaporated and purified by column chromatography to yield 197 mg of 2-[5-(L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:15]([OH:17])=O)([CH3:3])[CH3:2].[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH:30][C:15]([C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[O:8][C:4]=3[CH:1]([CH3:2])[CH3:3])=[O:17])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC(C)c1oc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CC(C)c1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 16 above, 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1)=O.O.[NH2:14][NH2:15]>CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:14][NH2:15])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(OC)ccn1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccnc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
4-Methoxypyridine-2-carboxylic acid methyl ester (17.6 g, 0.105 mol) was dissolved in methanol (100 ml) and cooled to 0° C. before adding hydrazine hydrate (21 ml) dropwise over 10 min. The mixture was then refrigerated at 4° C. for 16 h. The resulting solid was filtered, washed with cold methanol and dried to afford 4-methoxypyridine-2-carboxylic acid hydrazide (14.3 g, 81%) as a white powder. 1H NMR (360 MHz, CDCl3) δH 3.89 (3H, s), 4.55 (2H, br s), 7.12 (1H, dd, J 3 and 6), 7.50 (1H, d, J 3), 8.42 (1H, d, J 6), 9.79 (1H, br s).
Reaction SMILES: [CH2:1]([O:3][C:4](C1N=C2N(CC3C=C4C(=CC=3)N=CC=C4)N=NC2=NC=1)=[CH2:5])[CH3:2].Br[C:27]1[N:32]=[C:31]2[N:33]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][C:47]=3[F:48])[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])[N:34]=[N:35][C:30]2=[N:29][CH:28]=1>>[CH2:4]([O:3][C:1]([C:27]1[N:32]=[C:31]2[N:33]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][C:47]=3[F:48])[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])[N:34]=[N:35][C:30]2=[N:29][CH:28]=1)=[CH2:2])[CH3:5]
Reactant: CC(c1cc2cccnc2cc1F)n1nnc2ncc(Br)nc21
Reactant: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C=C(OCC)c1cnc2nnn(C(C)c3cc4cccnc4cc3F)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound 52.3 from 6-(1-(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-7-fluoroquinoline. 1H-NMR (400 MHz, CDCl3) δ ppm 9.17 (9.17 (s, 1H), 8.90 (m, 1H), 8.10 (d, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.39 (dd, 1H), 6.82 (q, 1H), 5.56 (d, 1H), 4.56 (d, 1H), 4.04 (q, 2H), 2.30 (d, 3H), 1.48 (t, 3H). LCMS (method B): [MH]+=365, tR=2.55 min.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[Na+].[CH3:25][NH:26][CH3:27]>O1CCOCC1>[CH3:25][N:26]([CH3:27])[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (0.70 g), sodium iodide (0.1 g) and 50% aqueous dimethylamine (2.2 ml) in 1.4-dioxane (7 ml) was stirred at room temperature overnight and then evaporated in vacuo. After an addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (20:1) as an eluent to give N-(4-dimethylamino-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (0.35 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:6])[CH3:2].[CH2:27](O)[CH:28]=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:6])=[CH:27][CH2:28][OH:29])[CH3:2]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCO
Solvent: ClCCl
Product: CCOC(=O)C(C)=CCO
Yield: 90 %

Procedure:
886 g (2.44 mol) of 2-(triphenyl-phosphanylidene)-propionic acid ethyl ester in methylene chloride (4 L) was added dropwise into a refluxing solution of glycoaldehyde dimer (140 g, 1.17 mol) in methylene chloride (6 L). After refluxing for 4 h, the solvent was evaporated. Resulting crude product was fractionated (bp 108–114° C. at 2 mmHg) to give 304 g (90%) pure product as an oil. 1H-NMR (300 Hz CDCl3) δ 6.88 (t, 1H, CH), 4.35 (d, 2H, CH2OH), 4.20 (q, 2H, OCH2), 1.85 (s, 3H, CH3), 1.30 (t, 3H, CH3).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:9]1[C:10]([NH:12][CH:13]1[CH:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:15](=[O:26])[CH2:14]1)=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:9]1[C:10]([NH:12][CH:13]1[CH:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:16][C:15](=[O:26])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(NC(=O)C2CCCCN2)C(OCc2ccccc2)O1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
N—(N-tert-Butoxycarbonylpipecolyl)-4-amino-5-benzyloxy-2-oxo-tetrahydrofuran (654 mg) was dissolved in 15 ml of 25% trifluoroacetic acid in dichloromethane and stirred at room temperature. The mixture was concentrated to give a gummy residue. The residue was dissolved in dichloromethane and washed with 10% sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 422 mg of the title compound as a beige solid. 1H NMR (500 MHz, CDCl3) δ 7.38 (m, 5H), 7.15 (d, 1H), 5.55 (d, 1H), 4.95-4.8 (m, 1H), 4.78 (m, 1H), 4.65 (d, 1H), 4.45 (m, 1H), 3.2 (m, 0.5H), 3.05 (m, 0.5H), 2.95 (m, 0.5H), 2.85 (m, 0.5H), 2.65 (m, 1H), 2.55-2.38 (m, 1H), 1.95 (m, 1H), 1.8 (m, 1H), 1.6 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)[C:14]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 9) (3.80 g, 8.57 mmol) was suspended in 190 ml of acetone and cooled to 0° C. 48 ml of 5.0N hydrochloric acid was added slowly through an additional funnel. The ice-water bath was removed and reaction mixture was stirred at room temperature overnight. Acetone was removed and aqueous layer was neutralized with 1.0N sodium hydroxide to PH about 10. The solid was filtered and dried to give 2.926 g of 4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-Cyclohexanone. 1H NMR (CDCl3) 2.39(m, 2H), 2.62(m, 6H), 5.30(m, 1H), 6.08(bs, 2H), 7.09(m, 2H), 7.15(m, 3H), 7.42(m, 2H), 7.64(d, J=8.70 Hz, 2H), 8.39(s, 1H); LC/MS (MH+=400).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].F[C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=1)[CH:36]=[O:37].O>CN(C)C=O>[F:1][C:2]([F:22])([F:23])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=2)[CH:36]=[O:37])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol (500 mg, 1.44 mmol) in N,N-dimethylformamide (7.2 mL), potassium carbonate (300 mg, 2.17 mmol) was added. Under ice-cold conditions, the resultant mixture was added with 5-fluoro-2-nitrobenzaldehyde (220 mg, 1.30 mmol) and stirred at 60° C. for 1 hour. The reaction solution was cooled down to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 5-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrobenzaldehyde (576 mg, yield 89%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([OH:13])=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=1>C(#N)C>[CH3:9][N:6]1[C:7]([CH3:8])=[C:2]([F:1])[C:3]([OH:14])=[C:4]([C:11]([NH:27][C:28]2[CH:33]=[N:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:13])[C:5]1=[O:10]
Reactant: N#Cc1ccc(N)cn1
Reactant: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1c(F)c(O)c(C(=O)Nc2ccc(C#N)nc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
500 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid was dissolved in 5 ml of acetonitrile, and 403 mg of carbonyldiimidazole was added thereto. The mixture was stirred for 1 hour under heat refluxing condition, 297 mg of 5-amino-2-cyanopyridine was added, and the mixture was further stirred for 1 hour under heat refluxing condition. The reaction mixture was cooled to room temperature, and the resulting crystals were collected by filtration to obtain 460 mg of 1,6-dimethyl-5-fluoro-4-hydroxy-2-oxo-N-(6-cyano-3-pyridyl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 12) represented by the formula:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=1)([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:68]([N:70](C)[C@@H:71]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[CH2:72]C)=O)N=2)CC1)=O>C(#N)C>[CH3:68][N:70]([C@@H:71]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH3:72])[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: C[C@H](c1ccccc1)N(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(1,1-Dimethylethyl) 4-(5-carboxy-2-thiazolyl)-1-piperazinecarboxylate (i.e. the product of Example 4, Step B) (1.0 g, 3.2 mmol) was suspended in 10 mL of dry acetonitrile and treated with triethylanaine (892 μL, 6.4 mmol) to give a homogeneous solution. To this was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.33 g, 3.5 mmol) followed by (α,R)—N,α-dimethylbenzenemethanamine (i.e. the product of Example 1, Step C) (200 μL, 1.38 mmol). The reaction mixture was stirred at ambient temperature for 3 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.38 g of an orange foam. Purification by silica gel chromatography using an ethyl acetate/hexanes gradient from 1:9 to 100:0 gave 0.78 g of the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)[C:4]=2[CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:19]=[N:18][C:5]3[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:4]=3[CH:3]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1
Yield: 42 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (293 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as a pale yellow solid (42% yield). M.p. 178-179° C., LCMS: m/z=374.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.38 (t, J=7.1) Hz, 3H), 3.40 (t, J=5.1 Hz, 2H), 3.60-3.63 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.48 (s, 2H), 6.85 (s, 1H), 7.27-7.49 (m, 5H), 7.43 (d, J=8.3 Hz, 2H), 7.73 (d, J=2.0 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCCCCCC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCCCCCC(C)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from 2-octanone and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cccc(OC)c2o1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)c1cc2c(S(=O)(=O)Cl)ccc(OC)c2o1
Yield: 80 %

Procedure:
There was reacted 1.7 g (8.25 mmole) of 2-methoxycarbonyl-7-methoxybenzofuran with chlorosulfonic acid as in Example 1, yielding 2 g of 2-methoxycarbonyl-4-chlorosulfonyl-7-methoxybenzofuran (yield: 80%, MS (m/z): 304 (M+), 269, 238 and 210). The obtained chlorosulfonyl compound was reacted wit glycine ethyl ester hydrochloride as in Example 1 to give an ester compound (yield: 88%, MS (m/z): 371 (M+), 340, 298 and 269), which was then hydrolyzed to give 2-carboxy-4-(N-carboxymethylsulfamoyl)-7-methoxybenzofuran (colorless needles, yield: 86%). The physical constants are shown in Table 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[Br-:20]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:20][CH:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:19]
Reactant: COc1ccc(C(=O)CCCc2ccccc2)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(Br)CCc2ccccc2)cc1
Yield: 89.4 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-methoxy-phenyl)-4-phenyl-butan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. The crude product obtained was recrystallized with a mixture of petroleum ether and ethyl acetate (2:1) to give a product as a white solid in a yield of 89.4%, mp: 65-66 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.38˜2.52 (2H, m, CH2), 2.75˜2.90 (2H, m, CH2), 3.88 (3H, s, OCH3), 5.03 (1H, t, J=8.00 Hz, CHBr), 6.93 (2H, d, J=9.2 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.91 (2H, d, J=9.20 Hz, ArH); ESI-MS m/e (%): 334.0 (M+2, 1), 332.0 (M, 1), 229.9 (53), 227.9 (53), 135.0 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18]([OH:20])=O)=[N:10]2)=[N:7][CH:8]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=2)[N:10]=1)=[O:20])([CH3:26])[CH3:25]
Reactant: CC(C)(N)CO
Reactant: COc1ccc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)nc1
Product: COc1ccc(-n2nc(C(=O)NC(C)(C)CO)c3c2[C@@H]2C[C@@H]2C3)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(5-methoxy-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=343.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.24 (td, J=8.0, 4.8 Hz, 1H), 1.40 (s, 3H), 1.41 (s, 3H), 2.23-2.29 (m, 1H), 2.72-2.76 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.00 (dd, J=16.6, 6.2 Hz, 1H), 3.69 (s, 2H), 3.91 (s, 3H), 4.83 (bs, 1H), 6.95 (s, 1H), 7.36 (dd, J=9.0, 3.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 8.15 (d, J=2.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1([O:11][CH3:12])[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[Cl:13][CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23](=[N:27][O:28][CH3:29])[C:24](O)=[O:25])[N:22]=1)=[O:16].C(=O)([O-])O.[Na+:34].P(=O)(O)(O)O>O.O1CCCC1>[Cl:13][CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23](=[N:27][O:28][CH3:29])[C:24]([NH:1][C:2]2([O:11][CH3:12])[CH2:5][N:4]([S:6]([O-:9])(=[O:7])=[O:8])[C:3]2=[O:10])=[O:25])[N:22]=1)=[O:16].[Na+:34]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: COC1(N)CN(S(=O)(=O)O)C1=O
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1(OC)CN(S(=O)(=O)[O-])C1=O)c1csc(NC(=O)CCl)n1

Procedure:
In 1 ml of water is dissolved 30 mg of the above 3-amino-3-methoxy-2-oxoazetidine-1-sulfonic acid, and to the solution are added a solution of 89 mg of the acid chloride prepared from 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer) in 1 ml of tetrahydrofuran and 36 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. The mixture is further stirred at room temperature for 20 minutes and adjusted to pH 5.8 with phosphoric acid. After removal of tetrahydrofuran under reduced pressure, the water layer is washed with ethyl acetate and purified by Amberlite XAD-II chromatography. The above procedure yields 28 mg of sodium 3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-methoxy-2-oxoazetidine-1-sulfonate (syn-isomer) which is the same compound as the one described in Example 9.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:27]=[C:26]4[O:28][CH2:29][C:23]5[C:24]6[C:25]4=[C:16]([CH2:17][O:18][C:19]=6[CH:20]=[C:21]([C:30]4[NH:34][C:33]([C@@H:35]6[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]6[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[N:32][CH:31]=4)[CH:22]=5)[CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:55][O:56][C:57]([NH:59][C@@H:60]([CH:64]([CH3:66])[CH3:65])[C:61](O)=[O:62])=[O:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:55][O:56][C:57]([NH:59][C@@H:60]([CH:64]([CH3:66])[CH3:65])[C:61]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:15]=[C:16]3[CH2:17][O:18][C:19]4[C:24]5=[C:23]([CH:22]=[C:21]([C:30]6[NH:34][C:33]([C@@H:35]7[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]7[C:41](=[O:54])[C@H:42]([NH:49][C:50]([O:51][CH3:52])=[O:53])[C:43]7[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=7)=[N:32][CH:31]=6)[CH:20]=4)[CH2:29][O:28][C:26]([CH:27]=2)=[C:25]35)=[CH:12][N:13]=1)=[O:62])=[O:58]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 1 h

Procedure:
A mixture of methyl (R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (90 mg, >0.123 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (24 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1 hour. An additional 0.135 mmol of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and HATU were added and stirring continued for 4 hours. The crude product was purified by reverse phase HPLC to product (28 mg) as a trifluoroacetate salt.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1)#[N:2].[OH-:24].[K+].OO>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[N:5]([CH2:4][CH2:3][C:1]([NH2:2])=[O:24])[N:6]=[CH:7][CH:8]=3)=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: N#CCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Agent: OO
Agent: [K+]
Product: NC(=O)CCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Reaction of 3-dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone with 2-cyanoethylhydrazine as described above gave 1-(2-cyanoethyl)-5-[4-(4-fluorophenoxy)phenyl]pyrazole. Reaction of a solution of the nitrile with 10 mL of a 20% aqueous KOH solution and 4 mL of an aqueous 30% H2O2 solution at reflux gave 64 mg of the amide as a white solid, mp 118-120° C. 1H NMR (CDCl3): δ7.54 (d, 1H, J=1.8 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.10-6.98 (m, 6H), 6.26 (d, 1H, J=1.8 Hz), 6.08 (br s, H), 5.30 (br s, 1H), 4.39 (t, 2H, J=6.6 Hz), 2.86 (t, 3H, J=6.6 Hz).