Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H](CC1C=CC(C2C=CC=CC=2F)=CC=1)C(OC)=O.N[C@@H](CC1C=CC(OCC#CC)=CC=1)C(OC)=O.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C@H:53]([NH:58][C:59]([C@@H:61](/[CH:75]=[CH:76]/[CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][S:83]([CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])(=O)=O)[C@@:62]([OH:74])([CH2:70][CH2:71][O:72][CH3:73])[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[O:60])[C:54]([O:56][CH3:57])=[O:55])=[CH:48][CH:47]=1.FC1C=CC=CC=1C1C=CC(C[C@H](NC([C@@H](/C=C/CCCCCCS(CCCCCCC)(=O)=O)[C@@](O)(CCOC)C(O)=O)=O)C(OC)=O)=CC=1>>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C@H:53]([NH:58][C:59]([C@@H:61](/[CH:75]=[CH:76]/[CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][S:83][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[C@@:62]([OH:74])([CH2:70][CH2:71][O:72][CH3:73])[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[O:60])[C:54]([O:56][CH3:57])=[O:55])=[CH:48][CH:47]=1
Reactant: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccc2F)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Agent: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccc2F)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Agent: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2F)cc1
Product: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccc2F)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(2′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (ESI (LC/MS positive mode) m/z 744 (M+H); Rt 3.77 min.) was synthesized by using methyl (S)-2-amino-3-(2′-fluoro-biphenyl-4-yl)-propionate and conditions at 50° C., for 1.5 days instead of methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate and the conditions in Step C-6. Then, tert-butyl (E)-(2S,3S)-3-[(S)-2-(2′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate was first synthesized (ESI (LC/MS positive mode) m/z 776 (M+H); Rt 2.23 min.) under conditions similar to those in Step C-7. Subsequently, (E)-(2S,3S)-3-[(S)-2-(2′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoic acid (No. 5540578) was synthesized by the reaction under conditions similar to those in Step C-8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]([O:25]CC)=[O:24])[CH:15]([C:19]([F:22])([F:21])[F:20])[O:16]3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]([OH:25])=[O:24])[CH:15]([C:19]([F:21])([F:22])[F:20])[O:16]3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(=O)c3cccnc3)cc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2ccc(C(=O)c3cccnc3)cc2OC1C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
The ester from Step 1 (38 mg, 0.08 mmole) was dissolved in 0.5 mL methanol and 0.5 mL THF. Sodium hydroxide (2.5 N) (0.2 mL, 0.5 mmole) was added to above solution and stirred at 50° C. for 4 h. The crude was purified by RPHPLC with 45% ACN in water to afford a white solid (15 mg,41%): LCMS m/z 350.05 (M+H). 1H NMR (DMSO-d6/400 MHz) 8.87 (s, 1H), 8.83 (d, 1H, J=6.8 Hz), 8.11 (d, 1H, J=10.4 Hz), 7.94 (s,1H), 7.69 (d, 1H, J=14 Hz), 7.60 (m, 1H), 7.42 (d, 1H, J=10.4 Hz), 7.34 (s, 1H), 6.03 (q, 1H, J=9.6 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=2[CH:32]=O)=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=2[CH2:32][N:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[CH:20][CH:19]=1
Reactant: O=C1CCNCC1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCC(=O)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
A suspension of the hydrochloride salt of 4-oxopiperidine (273 mg, 2.01 mmol) and DIPEA (351 μL, 2.01 mmol) was stirred in DCE (9.0 mL) at room temperature for 10 minutes. 2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde (500 mg, 2.01 mmol) was then added, followed by NaBH(OAc)3 (426 mg, 2.01 mmol) and activated molecular sieves (˜1 g). The resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was then filtered through a plug of Celite, rinsing with EtOAc. The filtrate was washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic layer was dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography on silica gel to afford the title compound (262 mg, 40% yield). MS (ESI) m/e (M+H+): 331.88
Reaction SMILES: C([NH:4][CH2:5][CH:6]([F:23])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]2=[N:19][NH:20][C:21](=[O:22])[N:10]2[CH:9]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1>C(Cl)CCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][CH2:5][CH:6]([F:23])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]2=[N:19][NH:20][C:21](=[O:22])[N:10]2[CH:9]=1
Reactant: C=CCNCC(F)Cc1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Solvent: ClCCCl
Product: NCC(F)Cc1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
6-[3-(allylamino)-2-fluoropropyl]-9-chloro[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (6-4)(18 mg, 0.054 mmol, 1.0 equiv) and DMBA (25.2 mg, 0.16 mmol, 3.0equiv) and tetrakis(triphenylphosphine)palladium(0) (3 mg, 2.60 μmol, 0.05 equiv) were suspended in ClCH2CH2Cl (1 mL). The resulted yellow suspension was heated at 50° C. LCMS at 5 hours showed mostly product. The crude was purified with reverse phase HPLC H2O/CH3CN gradient w/0.1% TFA present) to afford the pure product (6-5). 1H NMR (500 MHz, CD3OD) δ 8.26 (d, 1H, J=2.3 Hz), 7.88 (d, 1H, J=8.5 Hz), 7.72 (dd, 1H, J=8.5, 2.3 Hz), 7.61 (s, 1H), 5.19-4.94 (dm, 1H, J=50.0 Hz), 3.52-3.33 (m, ˜4H, overlap w/solvent peak). LRMS m/z (M+H) 295.3 found, 295.1 required.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]([CH3:12])([CH3:13])[CH:10]=[O:11]
Reactant: COC(=O)CCC/C=C\C(C)(C)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCC/C=C\C(C)(C)C=O
Reaction time: 5 h
Yield: 77.1 %

Procedure:
0.530 g (2.65 mmoles) of (Z)-8-Hydroxy-7,7-dimethyl-5-octenoic acid methyl ester in 5 ml of methylene chloride was added slowly to a mixture of CrO3 (2.1 g; 21 mmol) and pyridine (3.5 g; 42 mmol) suspended in 55 ml of methylene chloride at room temperature. The reaction mixture was stirred for 5 hrs. The dichloromethane phase was decanted, and the precipitate was washed three times with ether. The organic phases were combined, washed with chilled 1 N sodium hydroxide, 1 N sulfuric acid, saturated sodium bicarbonate solution and brine then dried (MgSO4) and concentrated to give 0.53 g of crude material. Purification by chromatography or a silica gel column afforded 0.405 g (77.1%) of pure (Z)-8-Oxo-7,7-dimethyl-5-octenoic acid methyl ester (100% pure, by GC-analysis).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@H:34]4[CH2:39][O:38][CH2:37][CH2:36][N:35]4C(OC(C)(C)C)=O)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@H:34]4[CH2:39][O:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@H]4COCCN4C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@H]4COCCN4)c3)c3ccccc23)cc1
Yield: 51.3 %

Procedure:
A solution of the carbamate (8) (28 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to capture and release on SCX and then triturated from diethyl ether (10 mL) to afford the title compound (Example 10) as an off-white solid (13 mg, 53%): m/z 634 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlapping m), 3.56-3.64 (4H, overlapping m), 3.82 (1H, m), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, overlapping m), 7.92 (1H, m), 8.28-8.35 (3H, overlapping m), 8.58 (1H, br s), 8.79 (1H, br s), 10.09 (1H, br s) [partial assignment].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N:5]1([C:11]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([OH:17])[CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>[N+](C1C=CC=CC=1)([O-])=O>[F:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([C:14]1[C:13]([OH:18])=[CH:12][C:11]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:16][C:15]=1[OH:17])=[O:23]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Oc1cc(O)cc(N2CCOCC2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1cccc(F)c1F)c1c(O)cc(N2CCOCC2)cc1O
Temperature: 110 °C
Yield: 22 %

Procedure:
Aluminum chloride (905 mg, 6.79 mmol) was added to a solution of 5-morpholin-4-yl-benzene-1,3-diol in nitrobenzene (8 mL), and the mixture was heated to 110° C. A solution of 2,3-difluorobenzoyl chloride in nitrobenzene was added slowly, and the mixture was heated at 100° C. for 12 h. The majority of the nitrobenzene was removed via short-path vacuum distillation. The black residue was dissolved in water/EtOAc (1:1, 20 mL). The aqueous component was extracted with EtOAc (3×40 mL), and the combined extracts were dried (MgSO4) and filtered through a ¾-inch silica gel plug. The filtrate was concentrated and purified via Biotage chromatography (100% hexanes to 30% EtOAc/hexanes) to yield 196 mg (22%) of (2,3-difluorophenyl)-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)methanone. 1H NMR (CDCl3, 400 MHz) δ: 7.30-7.10 (comp., 3H), 5.85 (s, 2H), 3.85-3.75 (m, 4H), 3.42-3.38 (m, 4H).
Reaction SMILES: C([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14](=[CH2:29])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C>CO.[OH-].[Na+]>[OH:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14](=[CH2:29])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7]
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(C)=O)[C@]2(C)C1=CC(=O)[C@@H]1C[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(C)=O)[C@]2(C)C1=CC(=O)[C@@H]1C[C@@H]12
Yield: 85 %

Procedure:
Under argon, 500 mg of 17α-acetoxy 1α,2α-methylene-6-methylene-4-pregnene-3,20-dione is agitated for 16 hours in 30 ml of methanol and 16 ml of 5% sodium hydroxide solution. The mixture is poured on an ice water-sodium chloride solution and worked up as usual. The crude product is purified on 50 g of silica gel with a hexane-acetone gradient, thus isolating 380 mg of 17α-hydroxy-1α,2α-methylene-6-methylene-4-pregnene-3,20-dione.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[V]>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [V]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 85 °C

Procedure:
Vanadium pentoxide (V2O5) (229 g) was added to water (500 mL), to thereby yield a mixture, and an aliquot of oxalic acid (477 g) was added to the mixture with stirring at 80-90° C. so as to dissolve the vanadium compound, to thereby yield a solution of vanadium oxalate. Another aliquot of oxalic acid (963 g) was added to water (400 mL), and the resultant mixture was heated to 50-60° C. To the mixture, a solution of chromic anhydride (CrO3) (252 g) in water (200 mL) was added under sufficient stirring so as to dissolve the components, to thereby yield a solution of chromium oxalate. The thus-yielded solutions were mixed at 50-60° C., to thereby prepare a V—Cr-containing solution. To the V—Cr-containing solution, a solution of phosphomolybdic acid (H3(PMo12O40).20H2O) (41.1 g) dissolved in water (100 mL) and a solution of potassium acetate (CH3COOK) (4.0 g) dissolved in water (100 mL) were added. Subsequently, a 20 wt. % aqueous silica sol (containing 0.02 wt. % of Na2O) (2,500 g) was added, to thereby yield a slurry.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]3[CH:16]=[C:15](OC)[CH2:14][O:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]3[CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:14][O:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COC1=CC(=C2C(=O)Nc3cc(F)ccc32)OC1
Solvent: CCO
Product: O=C1Nc2cc(F)ccc2C1=C1C=C(N2CCOCC2)CO1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-methoxy-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.40 mmol) and morpholine (0.5 mL, 5.7 mmol) in 20 mL of EtOH was heated at reflux for 16 hours. The mixture was cooled to room temperature. The precipitates were filtered, rinsed with EtOH and dried in vacuum to give 6-fluoro-3-(4-morpholin-4-yl-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one as a pale yellow powder. Yield: 55 mg, 45%.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH:23]2[CH2:25][CH2:24]2)[CH2:18][CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH:23]1([N:19]2[C:20]3[C:15](=[CH:14][C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=4)=[CH:22][CH:21]=3)[C:16]([CH3:27])([CH3:26])[CH2:17][CH2:18]2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCN(C2CC2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Following general procedure L and using 4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester (Compound 61, 0.05 g, 0.13 mmol), 5 mL of ethanol and 5M sodium hydroxide solution (2 mL) followed by recrystallization from hot ethyl acetate, the title compound was obtained as a solid (0.030 g, 64%).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].C([O-])(O)=O.[Na+]>COCCOC.O>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:2]([C:9]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:11])[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NCC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
8.1 g (31.5 mmol) of Boc-(D)-Chg-OH were dissolved in 100 ml of 1,2-dimethoxyethane and then, at 0° C., NHS (3.7 g, 32.0 mmol) and DCC (7.0 g, 34.0 mmol) were added. After 6 h at RT, DCH was filtered off, and a solution of 2.3 g (31.0 mml) of glycine and 2.6 g (31.0 mmol) of NaHCO3 in 350 ml of water was added to the filtrate. Stirring at RT for 24 h was followed by concentration and extraction with 5% citric acid/ethyl acetate. Concentration of the organic phase resulted in 8.2 g (85.0%) of product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][O:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:28][O:27][C:26]4=[O:25])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)c(F)c3)CC2)c(C)c1
Yield: 13.8 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.96 g) described in Preparation Example 66 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.33 g), the title compound (367 mg) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:39]1[C:48]2[N:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][CH2:41][CH2:40]1)[CH2:12][CH2:13][CH2:14][C:15]1[N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:18][N:19]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][CH2:13][CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)[CH:39]1[C:48]2[N:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][CH2:41][CH2:40]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2CCCN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(c1)CCCC2N(CCCc1ncc[nH]1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75.5 %

Procedure:
To a solution of (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-[3-(1-trityl-1H-imidazol-2-yl)-propyl]-amine (101 mg, 0.161 mmol) in CH2Cl2 (1.6 mL) was added triethylsilane (0.38 mL, 2.4 mmol) followed by TFA (1.9 mL, 25 mmol), and the solution was stirred at room temperature for 21 h then concentrated in vacuo. The residue was dissolved in CH2Cl2 (15 mL) and washed with 1 N NaOH(aq) (10 mL). The aqueous phase was extracted with CH2Cl2 (2×10 mL), and the combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (150:5:1 CH2Cl2/MeOH/NH4OH) afforded COMPOUND 13 as a colourless foam (47 mg, 69%). 1H NMR (CDCl3) δ 1.62-1.93 (m, 4H), 2.02 (m, 1H), 2.16 (m, 1H), 2.58-2.88 (m, 6H), 3.91 (d, 1H, J=16 Hz), 3.98 (d, 1H, J=16 Hz), 4.02 (m, 1H), 6.86 (s, 2H), 7.18 (m, 3H), 7.43 (d, 1H, J=7.2 Hz), 7.55 (m, 2H), 8.55 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.52, 23.71, 25.96, 26.67, 29.43, 49.21, 51.07, 62.23, 115.28, 120.75, 122.41, 122.81, 135.47, 138.23, 138.86, 146.68, 148.71, 155.28, 157.49. ES-MS m/z 387 (M+H). Anal. Calcd. for C23H26N6.0.21H2O.0.36CH2Cl2: C, 66.67; H, 6.50; N, 19.97. Found: C, 66.77; H, 6.65; N, 19.69.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:56][C:46]=2[C:47]([N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[N:48][CH:49]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O[C@@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1N1CCC[C@@H](O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (R)-3-hydroxypiperidine and triethylamine in DMF yielding (R)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[CH3:16])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17](Cl)(Cl)=[O:18]>>[Cl:15][C:11]1[C:10]([CH3:16])=[C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[NH:1][C:17]2=[O:18])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1c(Cl)cccc1Nc1ncccc1N
Product: Cc1c(Cl)cccc1-n1c(=O)[nH]c2cccnc21

Procedure:
The acid solution obtained in Step B was treated with phosgene as described in Example 1, Step C, to provide 3-(3-chloro-2-methylphenyl)-1,3-dihydroimidazo[4,5-b]pyridin-2-one, m.p. 224°-225° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCCCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and n-butylamine as a pale-yellow solid (91%). NMR (400 MHz, DMSO-d6) δ 0.74 (t, J=8.0 Hz, 3H), 1.15-1.20 (m, 2H), 1.27 (s, 6H), 1.32-1.38 (m, 5H), 2.57 (s, 3H), 3.06-3.11 (q, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 8.10 (s, 2H). MS 402 (MH+).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=[O:8])[CH3:7])(=[O:4])=[O:3].[Br:9]Br>CC(O)=O.ClCCl>[Br:9][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(Br)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To a solution of methanesulphonylacetone (0.5 g, 3.67 mmol) in AcOH (7.34 mL) and dichloromethane (11.02 mL) in a round bottom flask was added bromine (0.189 mL, 3.67 mmol) dropwise. The reaction mixture was stirred at rt 90 min. Solvent was removed in vacuo. The residue was taken up in ether and washed with saturated aqueous sodium bicarbonate (2×). The organics were concentrated in vacuo. 1-Bromo-1-(methylsulfonyl)propan-2-one (0.332 g, 42% yield) was isolated as an oil.