Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11]1[S:10][CH2:16][C:14](=[O:15])[N:13]=1
Reactant: NCc1ccccc1Cl
Reactant: O=C1CSC(=S)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccccc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 10.4 %

Procedure:
To a suspension of 2-chlorobenzylamine (7.88 g, 55 mmol) and Rhodanine (6.65 g, 50 mmol) in acetonitrile (150 mL) was added DIPEA (19.15 mL, 110 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (13.5 g, 50 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (1 L) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). After shaking, lot of solids formed which was collected by filtration to obtain 1.25 g of the desired product. Then, the two layers were separated and the ethyl acetate layer was washed with brine solution and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate solution was removed partially and then it was stored in the refrigerator. The resulting solids were collected by filtration to afford 2.67 g of the desired product. Then, the aqueous layer was extracted with dichloromethane (2×150 mL). The dichloromethane extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage (40 m) silica gel column chromatography to obtain 4.2 g (total product 8.12 g, 67.5% yield) of 2-(2-chlorobenzylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C10H9ClN2OS (M+) 240.0124. found 240.0122.
Reaction SMILES: C(O[C:4]([CH:6]1[C:12](=O)[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=[O:5])C.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>C(O)(=O)C>[C:17]([O:16][C:14]([N:9]1[CH2:8][CH2:7][C:6]2=[C:4]([OH:5])[N:23]3[C:22]([N:21]=[C:12]2[CH2:11][CH2:10]1)=[CH:26][CH:25]=[N:24]3)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(O)c2CC1
Temperature: 80 °C

Procedure:
To 13.3 g (46.61 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 8 mL acetic acid was added 3.87 g (46.61 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 15 minutes. The resulting solid was collected by filtration and washed with TBME (3×10 mL) to give the desired product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:50]1[C:55]([F:56])=[C:54]([F:57])[C:53]([F:58])=[C:52]([F:59])[C:51]=1[F:60])=O>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29]([O:31][C:50]3[C:51]([F:60])=[C:52]([F:59])[C:53]([F:58])=[C:54]([F:57])[C:55]=3[F:56])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of #@5 (19.43 g, 37.03 mmol, 1 eq.) in dichloromethane (100 mL) and pyridine (5.86 g, 74.1 mmol, 2 eq.) was added pentafluorophenyl trifluoroacetate (20.7 g, 74.1 mmol, 2 eq.) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 52% ethyl acetate in heptane) to afford #174 (23.58 g, 92%) as a yellow oil. LC-MS (Protocol Q1): m/z 691.2 [M+H+], retention time=1.23 minutes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Br[CH2:8][C:9]([NH:11][C:12]1[C:29]([OH:30])=[C:28]2[C:15]([CH2:16][CH:17]3[C:26]([C:27]2=[O:31])=[C:25]([OH:32])[C:24]2([OH:33])[CH:19]([CH:20]([N:39]([CH3:41])[CH3:40])[C:21]([OH:38])=[C:22]([C:35]([NH2:37])=[O:36])[C:23]2=[O:34])[CH2:18]3)=[C:14]([N:42]([CH3:44])[CH3:43])[CH:13]=1)=[O:10]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:41][N:39]([CH3:40])[C@H:20]1[C@H:19]2[C@:24]([OH:33])([C:25]([OH:32])=[C:26]3[C@H:17]([CH2:18]2)[CH2:16][C:15]2[C:28](=[C:29]([OH:30])[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:13][C:14]=2[N:42]([CH3:43])[CH3:44])[C:27]3=[O:31])[C:23](=[O:34])[C:22]([C:35]([NH2:37])=[O:36])=[C:21]1[OH:38]
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reactant: C1CCONC1
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CN(C)c1cc(NC(=O)CN2CCCCO2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Yield: 39.6 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 2 g of [1,2]oxazinane, and 0.5 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2 ml acetonitrile to give 0.2 g of the product.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9](O)([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:15]O>>[CH3:15][O:3][C:1]([C:4]1[O:8][C:7](/[C:9](/[CH2:12][CH3:13])=[CH:10]/[CH3:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: CO
Reactant: CCC(O)(CC)c1ccc(C(=O)O)o1
Product: C/C=C(\CC)c1ccc(C(=O)OC)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(5-Carboxy-2-furanyl)pentan-3-ol (200 mg, 1.1 mmol) is dissolved in methanol (20 mL). HCl (g) is bubbled through the solution for 30 seconds. The reaction is stirred for 20 minutes at room temperature with no reaction. The solution is heated to 60° C. for 2 hours. The solution is concentrated and water is added followed by solid NaHCO3 until the pH was basic. Ethyl acetate is added and the solution is extracted. The organic layer is washed with water, dried over MgSO4 and filtered. The filtrate is concentrated to 213 mg of an orange oil which is used as is.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of lactone from Example 1, part A(5) (10.05 gm, 46.31 mmole) in THF-H2O (100 ml -18 ml) was treated slowly with 1M lithium hydroxide (60 ml). The reaction was stirred at room temperature under argon for 2 hours, concentrated and acidified to pH 6 with HCl. The solution was washed several times with ethyl acetate, acidified to pH 1 with HCl, saturated with sodium chloride and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to an oil which was crystallized from dichloromethane-hexane to afford 7.7 gm (71%) of the title compound.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:34]([O:41][CH:42]1[CH:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:46]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:45]([CH2:64][O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:44][C:43]1=[O:73])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[CH2:34]([O:41][C@@H:42]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:44][C:43]1([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1)[OH:73])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: Fc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(Cc3cc4cc(F)ccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 0.97 ml, 1.55 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-yl-methyl)-5-fluorobenzo[b]thiophene (520 mg, 1.41 mmol) in THF (15 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 10 minutes. To this solution, a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyl-tetrahydropyran-2-one (835 mg, 1.55 mmol) in THF (3 ml) was added dropwise. The mixture was stirred at −78° C. for one hour, and a saturated ammonium chloride aqueous solution was added thereto to stop the reaction. The reaction mixture was extracted with ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (770 mg, 66%).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:10])([CH3:9])[CH2:4][C:5](=[O:8])[O:6]2.[CH:11]([OH:14])([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:11]([O:14][CH:7]1[O:6][C:5](=[O:8])[CH2:4][C:3]([CH3:10])([CH3:9])[CH:2]1[OH:1])([CH3:13])[CH3:12]
Reactant: CC(C)O
Reactant: CC1(C)CC(=O)OC2OC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)OC1OC(=O)CC(C)(C)C1O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 7 g of 5,6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one, 35 ml of isopropanol and 350 mg of p-toluene sulfonic acid was stirred at room temperature for 23 hours and was diluted with water. The mixture was extracted with methylene chloride and the combined extracts were washed with aqueous saturated sodium bicarbonate solution, was dried and evaporated to dryness under reduced pressure. The 9.18 g of residue was chromatographed over silica and was eluted with a 1-1 mixture of hexane-ethyl acetate to obtain 2.597 g of dl 6-isopropoxy-5-hydroxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at 50° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27].N12CCCN=C1CCCCC2>CN(C=O)C>[C:26]([O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1ccc2ncccc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a suspension of 6-quinolinecarboxylic acid (12 g, 69 mmol) in DMF (100 mL) was added 1,1′-Carbonyldiimidazole (11.2 g, 69.3 mmol) and the mixture stirred at 40° C. for 1 hour. tert-Butanol (13 mL, 139 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (10.4 mL, 69.3 mmol) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature the reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate/heptane (1:3, 2×400 mL). The organic layer was dried over MgSO4 and concentrated to give quinoline-6-carboxylic acid t-butyl ester (14.54 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.63 (9H, s), 7.42-7.46 (1H, m), 8.10 (1H, d), 8.23 (1H, d), 8.26 (1H, d), 8.50 (1H, d), 8.96-8.98 (1H, m). LCMS: Retention time: 1.42 min. MS (ESI) m/z 230 (M+H)+
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)Cl.O.[CH:33](O)=[O:34]>>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][CH:33]=[O:34])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: O=CO
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(OC=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 60 %

Procedure:
4 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate in formic acid were heated to 60° C. for 6 hours and to 65° C. for an additional 3 hours (approx. 80% complete reaction) Methylene chloride and H2O were added to the mixture after transferring to a separation funnel. The methylene chloride layer was washed with water, NaHCO3, water and brine, dried over MgSO4 and its volume reduced to 3.8 g. The product was purified by silica gel chromatography (hexane/ethyl acetate) and identified as the above methyl formoyloxypentanoate ester with an overall yield of 60%.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:11]([CH3:20])[CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:33]=1)[C:27](N(OC)C)=[O:28]>>[Br:21][C:22]1[CH:33]=[C:26]([C:27]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C@H:11]([CH3:20])[CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:3]=2)=[O:28])[CH:25]=[N:24][CH:23]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: C[C@H](COC1CCCCO1)n1cc(I)c2cncnc21
Product: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 24 using 5-iodo-7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 17) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a brown oil in 66% yield, 215 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1=Nc2ccccc2C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1Nc2ccccc2C1(C)C
Reaction time: 5 h

Procedure:
Ethyl 3,3-dimethyl-3H-indole-2-carboxylate (4.00 g, 18.4 mmol) was dissolved in ethanol (20 ml) and activated palladium-on-charcoal (0.5 g) was then added to this solution. This mixture was hydrogenated for five hours. After filtration in order to remove the catalyst, the filtrate was dried (MgSO4) and the solvent removed in order to give a brown oil.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:15]([S:17]C)=S)[S:14][CH2:13][CH2:12][CH2:11][O:10]1.C>C(O)C>[CH3:1][NH:2][C:15]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[S:14][CH2:13][CH2:12][CH2:11][O:10]1)=[S:17]
Reactant: CSC(=S)C1(c2ccccn2)OCCCS1
Reactant: CN
Solvent: CCO
Product: CNC(=S)C1(c2ccccn2)OCCCS1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (6.5 cc) is added dropwise, in the course of 10 minutes and at a temperature between 34° C. and 37° C., to a solution of methyl 2-(pyrid-2-yl)-1,3-oxathiane-2-carbodithioate (17.5 g) in ethanol (60 cc). The reaction mixture is then stirred for 30 minutes at 2° C. The resulting crystals are filtered off, washed twice with petroleum ether (40 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product obtained (13.4 g) is dissolved in boiling ethanol (80 cc); decolourising charcoal (0.2 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 1 hour at a temperature of about 0° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 50° C. N-Methyl-2-(pyrid-2-yl)-1,3-oxathiane-2-carbothioamide (12 g), melting at 157° C., is thus obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][S:22]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)(=[O:24])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][P:36]([CH2:41]OS(C(F)(F)F)(=O)=O)([O:38][CH2:39][CH3:40])=[O:37])[CH3:34].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[CH:18][C:17]([N:21]([CH2:41][P:36](=[O:37])([O:38][CH2:39][CH3:40])[O:35][CH2:33][CH3:34])[S:22]([C:25]1[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=1)(=[O:24])=[O:23])=[CH:16]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(c1ccc2c(C(=O)NCc3ccccc3)cccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 200 mg 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-benzylamide, 180 mg diethylphosphonomethyltriflate (prepared analogously to Tetrahedron Letters 1986, 27, 1477) and 100 mg potassium carbonate in 4 ml N,N-dimethylformamide is stirred for three hours at ambient temperature. Then it is combined with ethyl acetate, washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (40:60 to 0:100) as eluant.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][C@@:8]([CH3:36])([C:17]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[N:24]=[C:23]([CH2:33][CH:34]=C)[CH:22]=1)=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:2]=C>ClCCCl>[CH3:36][C:8]1([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:7][C:6]2[CH:5]=[C:4]([CH:1]=[CH:2][CH:37]=2)[CH2:39][CH:38]=[CH:34][CH2:33][C:23]2=[CH:22][C:21](=[CH:26][C:25]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:29])=[O:30])=[N:24]2)[CH2:20][O:19][C:17]1=[O:18]
Reactant: C=CCc1cccc(C[C@](C)(NC(=O)OC(C)(C)C)C(=O)OCc2cc(CC=C)nc(N(C)S(C)(=O)=O)c2)c1
Solvent: ClCCCl
Product: CN(c1cc2cc(n1)CC=CCc1cccc(c1)CC(C)(NC(=O)OC(C)(C)C)C(=O)OC2)S(C)(=O)=O
Temperature: 120 °C

Procedure:
To a solution of {2-allyl-6-[methyl(methylsulfonyl)amino]pyridine-4-yl}methyl 3-allyl-N-(tert-butoxycarbonyl)-α-methylphenylalaninate (80 mg, 0.14 mmol) in degassed DCE (2.9 mL) was added Zhan (metathesis) Catalyst I (9.2 mg, 0.014 mmol). The reaction was heated to 120° C. in a microwave for 0.5 h. Concentration and flash, chromatography (silica gel, 0-50% EtOAc/hexanes) gave tert-butyl [(3EZ)-14-methyl-8-[methyl(methylsulfonyl)amino]-13-oxo-12-oxa-7-azatricyclo[14.3.1.16,10]henicosa-1(20),3,6(21),7,9,16,18-heptaen-14-yl]carbamate. MS: 530.4 (M+1) ES+
Reaction SMILES: [NH:1]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C@H:2]([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][O:4]C(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:1]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][OH:4]
Reactant: CC(C)(C)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H](CO)NN1CCOCC1

Procedure:
Morpholino-Ser(OAloc) was prepared from Ser(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:36])([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:20][C:19]=1[Cl:35])[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:36])([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[CH:20][C:19]=1[Cl:35])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@](C)(CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Yield: 98.8 %

Procedure:
To a solution of the compound of Example 11 (1.00 g) in THF (14 mL) was added under ice cooling lithium borohydride (229 mg), and then ethanol (1.4 mL) was added dropwise. The resultant solution was then stirred for 1 hour under ice cooling. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the target product (910 mg) as a colorless oil.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)=[CH:16][CH:15]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:43]>ClCCl>[ClH:43].[ClH:43].[ClH:43].[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)=[CH:16][CH:15]=1)=[O:11])[NH2:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(COC(=O)NNC(=O)OC(C)(C)C)cc3)nc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(COC(=O)NN)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a suspension of 4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}benzyl tert-butyl hydrazine-1,2-dicarboxylate (139.2 mg, 0.2797 mmol) in anhydrous dichloromethane (1.4 ml) was added 4M hydrogen chloride dioxane solution (1.4 ml, 5.6 mmol). After stirring at room temperature for 8 hrs, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The operation was repeated twice to azeotropically remove hydrogen chloride gas. The residue was dissolved in ethanol (6 ml), and ethyl acetate (30 ml) was added. The precipitated solid was filtered and dried under reduced pressure to give the title compound (105.3 mg, yield 74.3%) as a slightly yellow solid.