Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH2:4][CH2:3]1.C(#N)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.Cl>CCOCC.CCCCCC>[ClH:19].[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]([O:14][C:27](=[O:28])[NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[C:10]([F:13])([F:11])[F:12])[CH2:6][CH2:7]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=S1(=O)CCN(C[C@H](O)C(F)(F)F)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCS(=O)(=O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
In a 10 mL round-bottomed flask, (S)-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-1,1,1-trifluoro-propan-2-ol (120 mg, 485 μmol) was combined with acetonitrile (5.00 ml) to give a colorless solution. 1-Chloro-4-isocyanatobenzene (74.5 mg, 485 μmol) was added and the resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and purified on a silica column (hexane to 60% EtOAc/hexane gradient) to afford an oil. This oil was dissolved in ether and hexane and a 4N HCl solution (0.2 ml) was added and the mixture concentrated to afford 50 mg of (4-chlorophenyl)-carbamic acid (S)-1-(1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl)-2,2,2-trifluoroethyl ester hydrochloride as a white solid. (M+H)+=401 m/e.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: O=C1CCc2cc(F)ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(F)ccc32)CC1
Reaction time: 20 h
Yield: 70.2 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79) (0.090 g, 0.37 mmol), 4-butylpiperidine (0.078 g, 0.55 mmol), KI (0.091 g, 0.55 mmol), and K2CO3 (0.076 g, 0.55 mmol) in MeCN and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc) to give the title compound (92LH81) (0.090 g, 70%). 1H NMR (CD3OD) δ 7.19-7.15 (m, 1H), 6.99-6.97 (m, 2H), 3.97 (t, J=6.4 Hz, CH2), 2.90-2.87 (m, 4H), 2.59 (t, J=7.6 Hz, CH2), 2.38 (t, J=7.6 Hz, CH2); 1.96-1.78 (m, 4H), 1.67 (d, J=9.6 Hz, 2H), 1.29-1.22 (m, 9H), 0.90-0.88 (m, 3H); 13C NMR (CD3OD) δ 172.1, 160.0 (d, J=241.8 Hz), 136.7 (d, J=2.3 Hz), 130.6 (d, J=7.7 Hz), 117.8 (d, J=8.1 Hz), 115.9 (d, J=23.1 Hz), 114.6 (d, J=22.7 Hz), 57.0, 55.0, 41.6, 37.4, 36.9, 33.1, 32.4, 30.1, 26.2, 25.5, 23.9, 14.4; HPLC-MS (ammonium acetate) [M+H+=347.33.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[C:12](OC)[CH2:13][O:14][CH3:15])[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].[NH4+:19].[OH-]>CCO.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5]([OH:11])=[CH:6][C:7]([OH:8])=[N:19][C:12]=1[CH2:13][O:14][CH3:15]
Reactant: [NH4+]
Reactant: COCC(OC)=C(C(=O)CC(=O)OC)C(=O)OC
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1nc(O)cc(O)c1C(=O)OC
Temperature: 60 °C

Procedure:
2-(1,2-Dimethoxy-ethylidene)-3-oxo-pentanedioic acid dimethyl ester (29.8 g, 115 mmol) is dissolved in a solution of EtOH (250 mL), water (250 mL) and concentrated NH4OH(aq) (30 mL). The mixture is heated to 60° C. for 5 hours. The reaction mixture is cooled to room temperature and the EtOH removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified with concentrated hydrochloric acid, at which time a white precipitate appeared. The precipitate is collected and dried in a vacuum oven to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20][CH3:21])=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:21])=[O:34])=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: CSCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 34 from 5-((3,5-dichloropyridin-4-yl)thio)-N-(3-(methylthio)propyl)-4-nitrothiophene-2-carboxamide (100 mg, 0.23 mmol) and MCPBA (198 mg, 1.15 mmol). The titled product was obtained as a white solid (72.0 mg, 69% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.93 (1H, m), 8.41 (1H, s), 3.30 (2H, m), 2.80 (1H, m), 2.64 (1H, m), 2.50 (3H, s), 1.84 (2H, m). MS m/z: 454.08, 456.08 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][P:9]([CH2:13][C:14]([C:16]1([C:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)=[O:15])([O:11][CH3:12])=[O:10].[NH4+].[Cl-].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][P:9]([CH2:13][C:14]([C:16]1([C:19](=[CH2:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)=[O:15])([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCC(=O)C1(C(=O)CP(=O)(OC)OC)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CCCCC)C1(C(=O)CP(=O)(OC)OC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
To a vigorously stirred suspension of methyltriphenylphosphonium bromide (942 mg; 2.64 mmol) in tetrahydrofuran (6 ml) 1M solution of potassium tert-butoxide in tetrahydrofuran (2.64 ml; 2.64 mmol) was added dropwise at 0° C. To the next flask with a solution of 20 (255 mg; 0.88 mmol) in tetrahydrofuran (1.1 ml) 1M solution of potassium tert-butoxide (0.88 ml; 0.88 mmol) was added. After 20 min. both mixtures were warmed to room temperature and cooled again to 0° C. after 30 min. The solution of enolate of 20 was transferred via cannula to the stirred solution of ylide. After 1 h the mixture was warmed up to room temperature and stirred for next 4 h. Then saturated aqueous solution of NH4Cl (8 ml) and water (30 ml) was added and the mixture was extracted with diethyl ether (3×100 ml). Organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (2-15% acetone/benzene) to give 172 mg (0.60 mmol; 68% yield) of 6. 1H NMR (400 MHz, CDCl3) δ 0.89 (3H, t, J=6.9 Hz), 1.00 (2H, m), 1.27-1.35 (4H, m), 1.40 (2H, m), 1.48 (2H, m), 2.09 (2H, t, J=7.8 Hz), 3.78 (2H, d, JH-P=21.7 Hz), 3.78 (6H, d, JH-P=11.2 Hz), 5.14 (2H, m); 13C NMR (101 MHz, CDCl3) δ 14.0, 17.2, 22.5, 27.3, 31.7, 36.0, 37.0 (d, JC-P=135 Hz), 52.9 (d, JC-P=6.5 Hz), 115.4, 147.7, 201.8 (d, JC-P=7.0 Hz).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17].C(Cl)Cl>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:7]4[CH2:8][CH2:9][N:4]5[CH:3]=[N:2][N:1]=[C:5]5[CH2:6]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: c1nnc2n1CCNC2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Yield: 31.2 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.18 g) in DMF (8 mL) was added Ag2CO3 (1.12 g, 5 eq). The mixture was then added into a solution of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.21 g) in DMF (2 mL) at rt under stirring. The reaction mixture was heated at 80° C. for 36 h under N2, and cooled to room temperature. To the reaction mixture was added CH2Cl2 (100 mL), and the reaction mixture was washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (80.00 mg, 17.62%), HPLC: 88.57%. The title compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 484.2 (M+1); and 1H NMR (400 MHz, CDCl3) δ: 22.02-2.08 (m, 2H), 2.75 (t, J=13.20 Hz, 2H), 2.89 (t, J=10.80 Hz, 2H), 3.73 (s, 2H), 3.94 (s, 3H), 4.01 (t, J=10.80 Hz, 2H), 4.12 (t, J=12.40 Hz, 2H), 7.10 (m, 1H), 7.24 (s, 1H), 7.27 (t, J=6.00 Hz, 1H), 7.43 (s, 1H), 7.54-7.58 (m, 1H), 7.82-7.84 (m, 1H), 8.05 (s, 1H), 8.44 (s, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:34][C:35]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:36]=1[CH2:37][O:38][C:39]1[C:40]2[N:41]([C:45]([C:49]([OH:51])=O)=[C:46]([CH3:48])[N:47]=2)[CH:42]=[CH:43][CH:44]=1.Cl.Cl.[CH:59]([O:62][CH2:63][CH:64]([NH2:67])[CH2:65][NH2:66])([CH3:61])[CH3:60]>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:67][CH:64]([CH2:63][O:62][CH:59]([CH3:61])[CH3:60])[CH2:65][NH:66][C:49]([C:45]1[N:41]2[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH2:37][C:36]3[C:35]([F:34])=[CH:55][CH:54]=[CH:53][C:52]=3[F:56])[C:40]2=[N:47][C:46]=1[CH3:48])=[O:51]
Reactant: CC(C)OCC(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC(N)COC(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
125 mg (0.33 mmol) of HATU and 0.16 ml (0.90 mmol) of N,N-diisopropylethylamine were added to 95 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A in DMF (1.9 ml), and the mixture was stirred at RT for 20 min. At −20° C., 145 mg (0.54 mmol, 76% pure) of rac-3-isopropoxypropane-1,2-diamine dihydrochloride Example 224A in DMF (0.5 ml), to which 0.31 ml (1.8 mmol) of N,N-diisopropylethylamine had been added beforehand and which had been stirred at RT for 10 min, were then slowly added dropwise to the reaction mixture. The mixture was stirred at RT overnight. The mixture was then diluted with water/TFA and purified by prep. RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated and then re-purified by thick-layer chromatography (dichloromethane/methanol: 10:1). This gave 15 mg (12% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:14][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14]
Reactant: Brc1ccccc1Br
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1ccccc1C#CCCCO
Temperature: 85 °C
Reaction time: 144 h
Yield: 47.4 %

Procedure:
1,2-Dibromobenzene (10.94 g, 46.37 mmol), 4-pentyn-1-ol (9.36 g, 111.30 mmol), and bis(triphenylphosphine)palladium(II) dichloride (650 mg, 0.93 mmol) was stirred in triethylamine (150 mL) under nitrogen for 5 min. Copper(I) iodide (88 mg, 0.46 mmol) was added and the mixture was stirred for 4 hrs at 85° C. for 6 days. The mixture was cooled to room temperature and filtered through a celite pad, rinsed with ethylacetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol 30:1) to afford 5.33 g of the title compound. Yield: 47%. 1H NMR (300 MHz, D2O) δ 1.85 (m, 4H), 2.58 (t, J=6.6 Hz, 4H), 3.82 (t, J=6.0 Hz, 4H), 7.18 (m, 2H), 7.36 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 16.3, 31.4, 62.4, 80.2, 93.3, 126.0, 127.4, 131.8 ppm.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)O)ccc1C
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)OCc2ccccc2)ccc1C
Yield: 64.4 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-4-methylbenzoic acid (compound of Example 21) (0.5 g), 4-dimethylaminopyridine (0.05 g), benzyl alcohol (0.17 g) and dichloromethane (20 ml) are mixed, and to the mixture is added EDC.HCl (0.27 g) with stirring under ice cooling, and the mixture is stirred at room temperature overnight. Dichloromethane is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, and the mixture is washed with 5% aqueous sodium hydrogen carbonate solution, 10% hydrochloric acid and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate, and then ethyl acetate is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluent, water-acetonitrile). The fractions containing the desired compound are collected and the water and acetonitrile are distilled off under reduced pressure to give the title compound (0.40 g).
Reaction SMILES: CO.C(Cl)(Cl)Cl.[C:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH2:24][CH2:23]1)[C:13]2=[O:42])(=[O:9])[CH3:8].[BH4-].[Na+]>O>[CH3:39][O:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][C:34]=1[O:40][CH3:41])[N:31]=[CH:30][N:29]=[C:28]2[N:25]1[CH2:26][CH2:27][CH:22]([N:14]2[C:13](=[O:42])[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([CH:7]([OH:9])[CH3:8])[CH:11]=3)[N:16]([CH3:20])[C:15]2=[O:21])[CH2:23][CH2:24]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)=O)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)O)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 60 °C
Yield: 72.6 %

Procedure:
In a solvent mixture of 3 ml of methanol and 3 ml of chloroform was dissolved 200.0 mg (0.41 mmol) of Compound 63 obtained in Example 50, and sodium borohydride was added thereto in excess, followed by heating at 60° C. for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. To the residue was added ether, and the precipitated crystals were collected by filtration and dried to give 146.4 mg (yield: 73%) of Compound 60 as white crystals.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.N[C@H](C([NH:47][C@H:48]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH2:49]CCCNC(OCC1C=CC=CC=1Cl)=O)=O)C>O1CCCC1.C(Cl)(Cl)Cl.CO>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:47][C@H:48]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH3:49])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
At 0° C. the solution of 500 mg (2.326 mmol) of HCl Ala-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 500 mg (2.326 mmol) of Boc-Pro-OH, 300 mg (2.222 mmol) of 1-hydroxybenzotriazole and 480 mg (2.331 mmol) of dicyclohexylcarbodiimide in 30 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Ala-Lys(ClZ)-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 782 mg (89%) of the title compound as a colorless powder. Mp100–101° C., FAB-MS (m/e) 377[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C(O)(=O)C>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1)[NH:6][CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15]
Reactant: C=CC(=O)OC
Reactant: COc1cc(N)cc(OC)c1
Solvent: CC(=O)O
Product: COC(=O)CCNc1cc(OC)cc(OC)c1
Yield: 73.9 %

Procedure:
A mixture of 3,5-dimethoxyaniline (114.9 g., 0.75 mole), methyl acrylate (69.73 g., 0.81 mole) and glacial acetic acid (2 ml.) is refluxed for 20 hours. Reflux is discontinued and the reaction mixture is concentrated and then distilled in vacuo, to yield 106.8 g. (73.9%) of the title product, b.p. 174°-179° C. (0.7 mm.).
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2OC)(=[O:23])=[O:22])=[CH:17][CH:16]=1.ClC1C=C(S(N=C2C3C(=CC=CC=3)[C:47](=[O:54])C(Cl)=C2)(=O)=O)SC=1Cl>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:54][CH3:47])=[CH:29][CH:30]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2)cc1

Procedure:
5.2.41 N,N-dimethyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide (13f) was prepared according to the procedure for 13d except using 4,5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and 3-mercapto-N,N-dimethylpropanamide( ) which afforded the title compound 16.1 mg (48%) as a white solid, m.p.: ° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)=[O:2].[BH4-].[Na+].Cl>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[O:9][CH:8]([C:14]([F:16])([F:17])[F:15])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2cc(C=O)cc(C)c2OC1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(CO)cc(C)c2OC1C(F)(F)F
Temperature: 0 °C
Yield: 99.3 %

Procedure:
The solution of ethyl 6-formyl-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.9 g, 6.05 mmole) dissolved in a mixture of THF (10 mL) and ethanol (10 mL) was cooled to 0° C. (ice bath). Sodium borohydride (0.11 g, 3.00 mmole) was added to above solution portionwise over 30 minutes. The mixture was poured into 1.2 N HCl (10 ml) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil (1.9 g, 98%). No further purification was performed. GCMS m/z 316.0 (M+).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@@H:26]([C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[NH:27][OH:28])(=[O:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@H:26]([N:27]([OH:28])[CH:1]=[O:3])[C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)(=[O:23])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(C[C@H](NO)[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)[C@@H](CS(=O)(=O)N1CCc2ccc(Cl)cc2C1)[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (0.5 ml) and acetic anhydride (0.125 ml) was stirred at 0° C. for 1 hour, then a solution of (1R)-2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-N-hydroxy-1-[(2R)-tetrahydrofuran-2-yl]ethanamine (80 mg, 0.22 mmol) in anhydrous THF (5 ml) was added and the resulting mixture was stirred at RT for 1 hour. The mixture was evaporated under reduced pressure. The residue was taken up with MeOH (5 ml) and heated at 55° C. for 1 hour. The reaction mixture was evaporated under reduced pressure. After purification by crystallization in EtOAc/pentane, the title compound (22) was obtained as a white powder (37 mg, 43%). HPLC, Rt: 3.0 min (purity: 94.1%). LC/MS, M+(ESI): 389.3, M−(ESI): 387.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][CH2:12][CH3:13]
Reactant: COc1cccc(N)c1
Reactant: CCCC=O
Product: CCCCNc1cccc(OC)c1
Yield: 96.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-methoxyaniline (460 μl, 4.06 mmol) and butyraldehyde (360 μL, 4.06 mmol) were converted to the title compound (700 mg, 88%). 1H NMR (CDCl3) δ 7.36-7.20 (m, 1H), 6.56-6.32 (m, 3H), 4.02-3.95 (m, 3H), 3.87 (br s, 1H), 3.30 (t, J=7.0 Hz, 2H), 1.86-1.71 (m, 2H), 1.71-1.58 (m, 2H), 1.19-1.10 (m, 3H); MS(ESI+) m/z 179.9 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CO>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@@H]3O
Temperature: -78 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a solution of (−)-calanolide A (341 mg, 0.922 mmol) in anhydrous methylene chloride (5 mL) at −78° C. under N2 was added a solution of diethylamidosulfur trifluoride (DAST, 178 mg, 1.11 mmol) in methylene chloride (1 ml) and the resulting yellow solution stirred at −78° C. for 4 hours. The reaction was quenched with 0.5 mL methanol, then allowed to warm to room temperature. The solution was diluted with methylene chloride (20 mL), then washed with water (50 mL) and saturated brine (50 mL). After drying over magnesium sulfate, the solution was filtered and evaporated to provide a light yellow solid. TLC analysis (silica gel, 3% methanol in methylene chloride) showed two components, one fast-moving and one slow. The material was chromatographed through 80 g silica gel, eluting with 1% methanol in CH2Cl2, and the fractions containing the respective components combined and evaporated to afford 198 mg (61% yield) of compound 22 and 75.3 mg (22%) of (−)-calanolide B.