Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18]1)=[O:15].[H-].[Na+].Br[CH2:45][CH2:46][O:47][CH3:48]>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH3:48][O:47][CH2:46][CH2:45][O:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:18]1)=[O:15]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (215 mg) was dissolved in DMF (3 ml), sodium hydride (50% in oil, 30 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, 1-bromo-2-methoxyethane (55 μl) was added under ice-cooling, and the mixture was further stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (149 mg).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][C@@H:28]([CH3:41])[CH2:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]1=[O:40])(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C@@H:28]([CH3:41])[CH2:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]1=[O:40]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Cn1c(=O)ccc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)Cn1c(=O)ccc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
TBAF (1.2 g, 4.6 mmol) and (S)-1-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-1H-quinolin-2-one (0.31 g, 0.93 mmol) were dissolved in THF (5 mL) and stirred under an Argon atmosphere at rt overnight. The mixture was concentrated under reduced pressure and dissolved in EtOAc (30 mL). The solution was washed with water (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue thereof was filtered through silica to give the crude title compound (0.19 g), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2].[Sn](Cl)Cl.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CSc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)CC1=CSc2cc(N)ccc2N1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
A solution of (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (Example 8b, 5.8 g, 20.7 mmol) in ethanol (90 mL) was treated with tin (II) chloride and 1.0 M aqueous hydrochloric acid solution (3 mL). The reaction mixture was heated at 100° C. for 3 h. The suspension was allowed to cool and concentrated. The crude material was suspended in ethyl acetate (90 mL) and treated with 6.0 M aqueous sodium hydroxide solution (90 mL). The resulting precipitate was filtered. The filter cake was thoroughly washed with ethyl acetate, the filtrated was washed with brine solution, and concentrated in vacuo. The crude oil was purified by flash chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexanes) to afford the desired product, (7-amino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (2.38 g, 9.51 mmol, 46% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.1 Hz), 3.30 (s, 2H), 3.43 (bs, 2H), 4.08 (q, 2H, J=7.1 Hz), 4.52 (s, 1H), 6.39 (dd, 1H, J1=8.3 Hz, J2=2.7 Hz), 6.46 (d, 1H, J=2.3 Hz), 6.62 (d, 1H, J=7.6 Hz), 10.38 (bs, 1H). LC-MS (ESI) calcd for C12H14N2O2S [M+H+] 251.08, found 251.23 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chlorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.05–7.97 (3H, m), 7.45–7.37 (3H, m), 7.33–7.28 (1H, m), 7.21–7.18 (1H, m), 7.09–7.03 (1H, m), 5.42–5.31 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 445 (M+H)+, 443 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][S:4][CH2:3]1.S(Cl)(Cl)(=O)=O.Cl>C(Cl)Cl>[OH:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][S:4][CH:3]=1
Reactant: CC(=O)C1=CSCC1O
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cscc1O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2.88 Parts of 3-hydroxy-4-acetyldihydrothiophene are introduced into 20 parts by volume of dried methylene chloride; a solution of 1.7 parts by volume of sulfuryl chloride in 20 parts by volume of dried methylene chloride is added in the course of 10 minutes at 0° C. During the reaction, nitrogen is passed in, in order to expel the hydrochloric acid formed. After 30 minutes, the reaction mixture is worked up. The end product is isolated from the reaction mixture by the method described in Example 1c. 2.22 parts (77% of theory) of 3-hydroxy-4-acetylthiophene of melting point 44°-47° C. are obtained.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9](=[O:30])[CH:10]=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C1(C)C=CC=CC=1.[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH:39]=O>C(Cl)(Cl)Cl>[N:1]12[CH2:8][C:5]([C:9](=[O:30])/[CH:10]=[CH:39]/[C:38]([O:42][CH2:43][CH3:44])=[O:41])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C12CCCN(CC1)C2
Reactant: CCOC(=O)C=O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/C(=O)C12CCCN(CC1)C2
Temperature: 25 °C

Procedure:
5.00 g (12.09 mmol) of 1-(1-azabicyclo[3.2.1]oct-5-yl)-2-(triphenylphosphanylidene)-ethanone in solution in 20 ml of chloroform and 20 ml of toluene are introduced into a 100 ml three-necked round-bottomed flask. 1.36 g (13.3 mmol) of ethyl glyoxylate are subsequently added and the reaction medium is refluxed at ambient temperature for 15 min. The solvent is eliminated by evaporation under reduced pressure and the residue obtained is purified by silica gel column chromatography, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 89/2/0.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: OCc1ccc(Cl)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of (6-chloro-3-pyridyl)methanol (4.5 g, 31.3 mmol) and triethylamine (13.2 ml, 94.7 mmol) in dichloromethane (90 ml) was dropwise added methanesulfonyl chloride (3.6 ml, 46.5 mmol) over 45 minutes at −9° C. to 4° C. under an atmosphere of nitrogen gas, followed by stirring as it was. After 1 hour, the reaction mixture was elevated to room temperature. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated, to give the title compound (6.14 g, 88%) as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10])[CH:4]=[N:3]1.[OH-].[K+]>CO>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])[CH:4]=[N:3]1
Reactant: COC(=O)/C=C/c1cnn(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(/C=C/C(=O)O)cn1
Temperature: 70 °C
Yield: 72.5 %

Procedure:
(E)-methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (0.24 g, 1.45 mmol) was dissolved in MeOH (10 mL). A 1M solution of KOH (5.8 mL) was added and the mixture was heated at 70° C. overnight. The reaction mixture was then evaporated under reduced pressure and water (10 mL) was added to the residue. This solution was carefully acidified to pH 4 with a 3M aqueous solution of HCl. The carboxylic acid precipitated and was extracted with ethyl acetate. The EtOAc layer was washed with water (2×10 mL) and brine (1×15 mL). It was dried over sodium sulfate, filtered and evaporated under vacuum to give (E)-3-(1-methyl-1H-pyrazol-4-yl)acrylic acid as a white solid (160 mg). ES+(M+H)+153
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(O)(=O)/C=C/C(O)=O.[NH2:23][CH2:24][CH2:25][C:26]#[N:27].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH2:26][CH2:25][C:24]#[N:23])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N#CCCN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCC#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 200.3 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (4.95 g, 24.8 mmol) in DMF (25 ml) was added 3-aminopropionitrile fumarate (3.18 g, 12.4 mmol) and DIPEA (15 ml, 84.3 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum and the residue diluted with water (50 mL). It was extracted with EtOAc (3×100 mL) and the organic phase washed with brine solution and dried (Na2SO4). Removal of solvent gave 4-(2-cyanoethylamino)-3-nitro-benzoic acid methyl ester (6.19 g, 98.5%). MS-ESI m/z 250 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.8 (t, 2H), 3.8 (m, 2H), 6.9 (d, 1H), 8.2 (m, 1H), 8.5 (t, 1H), 8.9 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35](=[O:43])[NH:36][C:37]1([CH2:41]O)[CH2:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:43])[NH:36][C:37]1([CH2:41][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:38][CH2:39][CH2:40]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NC1(CO)CCC1
Product: CC(C)(C)OC(=O)NC1(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCC1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}cyclobutyl)carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and (1-hydroxymethylcyclobutyl)carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[C@H:69]12[CH2:75][C@@H:72]([CH2:73][CH2:74]1)[C@@H:71]([C:76]1[NH:80][C:79]3[CH:81]=[C:82]([C:85]4[CH:97]=[C:96]5[C:88]([C:89]6[CH:90]=[CH:91][C:92]([C:100]7[NH:104][C:103]([C@@H:105]8[CH2:109][CH2:108][CH2:107][N:106]8[C:110](=[O:121])[C@@H:111]([NH:116][C:117](=[O:120])[O:118][CH3:119])[C@H:112]([O:114][CH3:115])[CH3:113])=[N:102][CH:101]=7)=[CH:93][C:94]=6[C:95]5([F:99])[F:98])=[CH:87][CH:86]=4)[CH:83]=[CH:84][C:78]=3[N:77]=1)[NH:70]2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:70]1[C@H:71]([C:76]2[NH:80][C:79]3[CH:81]=[C:82]([C:85]4[CH:86]=[CH:87][C:88]5[C:89]6[C:94](=[CH:93][C:92]([C:100]7[NH:104][C:103]([C@@H:105]8[CH2:109][CH2:108][CH2:107][N:106]8[C:110](=[O:121])[C@@H:111]([NH:116][C:117]([O:118][CH3:119])=[O:120])[C@H:112]([O:114][CH3:115])[CH3:113])=[N:102][CH:101]=7)=[CH:91][CH:90]=6)[C:95]([F:99])([F:98])[C:96]=5[CH:97]=4)[CH:83]=[CH:84][C:78]=3[N:77]=2)[C@H:72]2[CH2:75][C@H:69]1[CH2:74][CH2:73]2)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@H]6N[C@@H]7CC[C@@H]6C7)[nH]c5c4)ccc2-3)[nH]1)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6[C@@H]7CC[C@H](C7)N6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)[C@@H](C)OC

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (2S,3R)-1-((S)-2-(5-(7-(2-((1R,3S,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 913.69 [M+H]+. (93 mg, 57%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:23][CH:20]3[CH2:22][CH2:21]3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NC1CC1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: Clc1nc(SCc2ccccc2)nc2nc(NC3CC3)sc12

Procedure:
Prepared by the method of Example 220, using the product of Example 219 and cyclopropanamine.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)/[CH:22]=[CH:23]/[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.O>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:19]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=4)[CH:23]=[CH:22][N:18]=3)=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Reactant: N=C(N)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: O=S(=O)(c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCOCC1
Temperature: 107.5 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A mixture of N-[4-(morpholin-4-ylsulfonyl)phenyl]guanidine (85 mg, 0.3 mmol), (2E)-3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (43 mg, 0.18 mmol), and potassium carbonate (83 mg, 0.6 mmol) in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) is stirred at 105 to 110° C. for 18 hrs. It is then cooled to room temperature, and diluted with water (15 ml). The resulting suspension is filtered, and the precipitate is washed with dilute citric acid and water, and then dissolved in ethyl acetate. The organic solution is passed through a pad of silica gel, and the filtrate is evaporated. The residue is triturated with a mixture of methylene chloride and hexanes to give 63 mg of a yellow solid; mp 240-241° C.; MS (ESI) m/z 465.2 (M+H); HRMS: calcd for C21H19F3N4O3S, 464.1130; found (ESI_FT), 465.11835.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:25]([NH:31][CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:25]([N:31]([CH3:32])[C:9]([C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCNC
Reactant: CC(=O)c1ccc(C(=O)O)o1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCCN(C)C(=O)c1ccc(C(C)=O)o1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 4.6 g. (0.03 mole) of 5-acetylfuran-2-carboxylic acid in 150 ml. of dichloromethane was added 3.3 g. (0.033 mole) of N-methylmorpholine. The resulting solution was cooled to -20° C., and 3.6 g. (0.033 mole) of ethyl chloroformate was added dropwise, with stirring. Stirring was continued for 1 hour at -15° C. and then 3.8 g. (0.033 mole) of n-hexylmethylamine was added dropwise at -20° C. The resulting mixture was stirred for 1.5 hours while being allowed to warm to room temperature. The reaction mixture was then washed with water, dried (Na2SO4) and evaporated in vacuo to give 7.5 g. of an oil. This oil was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate, to give 5.6 g. of the title amide as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:22]2[CH2:23][CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1ccc(CN2CC(CN3CCc4ccccc4C3)C(c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 0.010 mL of 1, 2, 3, 4-tetrahydro-isoquinoline and 25 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 25 mg of the title compound. RF : 0.51 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ2.51-2.78 (m, 9H), 2.94-3.00 (m, 3H), 3.40-3.69 (m, 4H), 6.91-6.94 (m, 1H ), 7.02-7.38 (m, 13H). Mass spec. (ESI): 383.2 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[CH:21]4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[N:45]([CH:47]=[O:48])C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:15]=[C:13]1[CH2:14][C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:47]([NH2:45])=[O:48])=[N:9][C:10]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)=[CH:16][C:11]=2[NH:12]1
Reactant: O=C1CC(c2cccc(I)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(3-iodo-phenyl)-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 7) (214 mg, 0.5 mmol), Pd(OAc)2 (4 mg, 3 mol %), PPh3 (8mg, 8 mol %) and HDMS (0.52 mL, 2.5 mmol) in DMF (2 mL) was stirred under CO atmosphere at 60° C. for 4 h. The mixture was taken up in EtOAc, washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over MgSO4. Removal of the solvent in vacuum left a dark brown solid, which was purified by silica gel column chromatography with EtOAc/MeOH 95:5. Obtained as a yellow-brown solid (97 mg).
Reaction SMILES: [CH2:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[NH:17][NH:16][C:15]2=[O:20])=[CH:10][CH:9]=1)\[CH3:7])[C:2]#[CH:3]>C(Cl)Cl>[CH2:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18](=[O:19])[N:17]=[N:16][C:15]2=[O:20])=[CH:12][CH:13]=1)\[CH3:7])[C:2]#[CH:3]
Reactant: C#CCO/N=C(\C)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Solvent: ClCCl
Product: C#CCO/N=C(\C)c1ccc(N2C(=O)N=NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To (E)-4-(4-(1-(prop-2-ynyloxyimino)ethyl)phenyl)-1,2,4-triazolidine-3,5-dione (I-6a: 46 mg, 0.169 mmol) in CH2Cl2 (1.69 mL) was added SiO2—HNO3 (100 mg). The mixture was stirred at room temperature for 30 minutes, filtered, concentrated in vacuo and dried to give (E)-4-(4-(1-(prop-2-ynyloxyimino)ethyl)phenyl)-3H-1,2,4-triazole-3,5(4H)-dione (24 mg, 53%) as a red solid. 1H NMR (400 MHz, CD3CN) δ ppm 2.31 (s, 3 H) 5.28 (s, 2 H) 7.38 (d, J=7.07 Hz, 1 H) 7.43 (t, J=7.20 Hz, 2 H) 7.46-7.54 (m, 4 H) 7.86-7.94 (m, 2 H). 1H NMR (400 MHz, CD3CN) δ ppm 2.31 (s, 3 H) 2.81 (t, J=2.40 Hz, 1 H) 4.84 (d, J=2.27 Hz, 2 H) 7.53 (d, J=8.84 Hz, 2 H) 7.93 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].O.[CH2:68]([OH:72])[CH2:69]CC>C(OC(=O)C)(=O)C>[C:68]([NH:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66])(=[O:72])[CH3:69]
Reactant: CCCCO
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CO[C@H]1C(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CNC(C)=O)[C@@H]1O
Reaction time: 0.58 h

Procedure:
A suspension of 39.0 mg (41.2 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid in 2.0 ml of acetic anhydride is placed in an ultrasonic bath (Branson 1200) at room temperature for 35 minutes. Water (2 ml) and n-butanol (2 ml) are added to the reaction mixture and the volatile materials removed under reduced pressure to a residue which is suspended in 2 ml of acetone and the suspension filtered through glass wool. The desired product (the acetone insoluble product) is recovered as a white solid by dissolving in 2 ml water followed by lyophylization.