Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]([C:8]1[C:9]([Cl:23])=[C:10]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[S:14](=[O:20])(=[O:19])[CH2:13][CH2:12][C:11]2([CH3:22])[CH3:21])(=[O:7])C.C(OCC)(=[O:26])C>O>[Cl:23][C:9]1[C:8]([C:5]([OH:26])=[O:7])=[CH:17][C:16]([CH3:18])=[C:15]2[C:10]=1[C:11]([CH3:22])([CH3:21])[CH2:12][CH2:13][S:14]2(=[O:20])=[O:19]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)O)c(Cl)c2c1S(=O)(=O)CCC2(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
3.6 Grams (85 mmol) of sodium hydroxide was dissolved in 70 ml of water, and 1.5 ml (29 mmol) of bromine was added with cooling with ice. Further, 2.8 g (9.3 mmol) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman-1,1-dioxide was added, and the mixture was stirred for 3 hours and then heated at 100° C. for 5 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was liquid-separated. An aqueous layer was adjusted to a pH of 1 by adding hydrochloric acid. The extraction of the aqueous layer was carried out by adding ethyl acetate, and an organic layer was dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to give 2.1 g (yield 75%) of 5-chloro-4,4,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: OCCCCc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(C)CCCCc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol and Dimethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-dimethyl-amine as brown oil, MS: 389 (MH+, 1Br).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:38]3[CH:37]=[N:36][CH:35]=[C:34]([Br:33])[CH:39]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: OB(O)c1cncc(Br)c1
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cncc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (0.134 g, 0.25 mmol), 3-bromo-pyridin-5-ylboronic acid (0.55 g, 0.27 mmol), Pd(PPh3)4 (0.014 g, 0.013 mmol), aq. 2M potassium carbonate solution (0.5 mL, 1.0 mmol) in degassed dioxane (2.0 mL) was heated in microwave at 80° C. for 30 minutes to give (S)-2-(2-(5-bromopyridin-3-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate. LCMS-ESI+: calc'd for C30H32BrClN2O3S: 617.1 (M+H+); found: 617.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NC(=O)CCC(=O)O)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.27 mmol, Example 120) and triethylamine (125 mg, 0.33 mmol) in tetrahydrofuran (5 mL), succinic anhydride (35 mg, 0.35 mmol, Aldrich,) was added and the mixture was refluxed for 2 hours. The mixture was cooled and the solid was filtered and dried to yield a white powder. 130 mg, 100%. MS (ES) MH+=478.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[CH:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1.C(O)C.II>COCCOC.C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:18]2[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:33][CH:34]=2)=[CH:11][CH:12]=1
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Nc1cccnc1NCc1ccc(Cl)cc1
Agent: II
Solvent: CCO
Solvent: COCCOC
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(Cl)cc3)cc2)S1

Procedure:
A procedure similar to that described in Example 18 was repeated, except that 1.20 g of 3-amino-2-(4-chlorobenzyl) aminopyridine (prepared as described in Preparation 53), 1.36 g of 5-[4-(2-oxoethoxy)benzyl]-thiazolidine-2,4-dione (prepared as described in Preparation 47), 3 ml of ethanol, 3 ml of acetic acid, 1.69 g of iodine and 25 ml of 1,2-dimethoxyethane were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent, to give 0.40 g of the title compound, melting at 211-213° C.
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]([CH3:21])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[CH3:20])=[O:6]>C1C=CC=CC=1>[CH3:1][NH:2][CH:4]([CH3:21])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[CH3:20])=[O:6]
Reactant: CN
Reactant: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1
Solvent: c1ccccc1
Product: CCCCOc1cc(C)c(NC(=O)C(C)NC)c(C)c1

Procedure:
To a cold stirred solution of 14.8 g. of monomethyl amine in 250 ml dry benzene was added (portionwise, keeping temperature below 10° ) 19.5 g (0.0594 mole) of 2-bromo-4'-butoxy-2',6'-dimethyl propionanilide (made according to the procedure in the first part of this example); this dissolved readily forming a clear solution. The mixture was heated to 70° for ca 1 hr. with stirring, at which point a white precipitate had separated and reflux became so vigorous that the reaction had to be controlled by external cooling.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=1)[CH3:22]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 300 g of 4-trifluoromethylcinnamic acid (J. Org. Chem. 43:980 (1978)) and 25 ml of concentrated sulfuric acid in 1.7 liters of ethanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-trifluoromethylcinnamic acid ethyl ester, mp 40°-41° C.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[CH2:7][C:8]#[N:9])[CH2:3][C:4]#[N:5]>C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:2]([CH3:1])[CH:6]([CH3:10])[CH2:7][C:8]=1[NH2:9])#[N:5]
Reactant: CC(CC#N)C(C)CC#N
Solvent: Cc1ccccc1
Product: CC1CC(N)=C(C#N)C1C
Yield: 94.1 %

Procedure:
5.6 g of potassium tert.butylate are refluxed for 60 minutes with 6.8 g of 3,4-dimethyladiponitrile in 50 ml of toluene. The cooled solution is washed with 50 ml of water and concentrated. There are obtained 6.4 g (94%) of 2-cyano-3,4-dimethyl-cyclopent-1-enylamine of melting point 92°-100° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][NH:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][NH:16][CH2:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCCNCc1cccc(OCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Next, to toluene (50 ml) were added 2-[(3-benzyloxyphenyl)methylamino]ethanol (10.3 g, 39.9 mmol), pivaloyl chloride (9.6 g, 79.8 mmol), and pyridine (7.6 g, 95.8 mmol). The mixture was stirred at room temperature for 1 hour and further at 85° C. for 2 hours. After pyridine hydrochloride was removed by filtration, the filtrate was concentrated. The product was purified by silica gel chromatography to give 2,2-dimethylpropionic acid 2-[(3-benzyloxyphenyl)methylamino]ethyl ester as a colorless oily matter (yield: 8.9 g (65.1%)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:21]([CH2:24][CH:25]3[CH2:27][CH2:26]3)=[N:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:21]([CH2:24][CH:25]3[CH2:26][CH2:27]3)=[N:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1c(NC[C@@H]2CCC[C@H]2c2ccccc2)ccn2c(CC3CC3)nnc12
Solvent: CCO
Product: Clc1c(NC[C@H]2CCC[C@@H]2c2ccccc2)ccn2c(CC3CC3)nnc12

Procedure:
Racemic trans 8-chloro-3-(cyclopropylmethyl)-N-((2-phenylcyclopentyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine was resolved by chiral preparative HPLC using a Chiralcel OJ 21×250 mm, 10 micron column with a 30% ethanol/0.1% diethylamine/heptane as the mobile phase to give 8-chloro-3-(cyclopropylmethyl)-N-(((1S,2S)-2-phenylcyclopentyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine, peak 1, eluting at 6.8 min. 1H NMR (400 MHz, METHANOL-d4) δ 8.05 (d, J=7.5 Hz, 1H), 7.33-7.20 (m, 5H), 7.20-7.08 (m, 1H), 6.60 (d, J=7.8 Hz, 1H), 3.48-3.36 (m, 1H), 2.97 (d, J=7.0 Hz, 2H), 2.83-2.66 (m, 1H), 2.40 (d, J=8.0 Hz, 1H), 2.23-2.05 (m, 2H), 1.93-1.76 (m, 3H), 1.57 (dd, J=12.7, 7.2 Hz, 1H), 1.26-1.13 (m, 1H), 0.70-0.56 (m, 2H), 0.39-0.25 (m, 2H). LCMS: M+1=381.16.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH:8]1([Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrCCCCCBr
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: BrCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 1,5-dibromopentane (16 gm, 69.97 mmol) in THF (20 ml) was added a solution of (Li2CuCl4 in ether, 14 ml) under nitrogen at 5-10° C. and stirred for 25 minutes. Cyclohexyl magnesium bromide (10 gm, 69.97 mmol) was added dropwise with stirring for about 30 minutes. The reaction mixture was stirred at 0° C. for another 1 h and stirred at room temperature for 12 hr. The reaction mixture was cooled to 0° C. in ice, saturated NH4Cl solution (20 ml) was added and the resulting mixture was extracted with EtOAc (4×25 ml). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane as an eluent. The pure product was an oily liquid (12.84 gm).
Reaction SMILES: [Si]([CH:18]([OH:44])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@:21]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@:20]1([C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:35])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[C:27]([C@@:21]1([OH:26])[C@:20]([C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([OH:35])[C@@H:19]([CH2:18][OH:44])[O:25][C@H:22]1[O:23][CH3:24])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@@H]1O[C@H](CO)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Yield: 89.1 %

Procedure:
A solution of 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside (849 mg, 1.39 mmol) and 1.0M tetrabutylammonium fluoride in THF (1.53 ml, 1.53 mmol) was stirred for 2 h at room temperature. After evaporation of the solvent, the residue was purified by silica gel column chromatography (Hx-EtOAc, 1:1) to yield 1-O-methyl 2,3-dibenzoyl-β-D-ribofuranoside [Rf =0.50 (Hx-EtOAc, 1:1), 461 mg, 89%] as thick syrup. 1H NMR (DMSO-d6) d 3.38 (s, 3H, --OCH3), 3.62 (m, 2H, H-5), 4.37 (q, J=5.2 Hz, 1H, H-4), 5.02 (pseudo t, J=6.0 and 5.3 Hz, 1H, exchangeable with D2O, 5-OH), 5.18 (s, 1H, H-1), 5.45 (m, 1H, H-2), 5.53 (t, J=5.2 Hz, 1H, H-3), 7.42-7.88 (m, 10H, Ar). Anal. Calcd for C20 H20O7 : C, 64.51; H, 5.41; Found: C, 64.37; H, 5.47.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:24]=[CH:23][C:11]3[NH:12][C:13]([C:15]4[C:19]([N+:20]([O-])=O)=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CN(C=O)C.[Pd]>[N:1]1([CH2:7][C:8]2[CH:24]=[CH:23][C:11]3[NH:12][C:13]([C:15]4[C:19]([NH2:20])=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole (1 mol. eq.) in DMF (36 vol.) under an atmosphere of nitrogen, was added 5% Pd/C (0.1 wt. eq.). The reaction vessel was charged with hydrogen and stirred at ambient temperature for 24 hours. The mixture was then filtered through celite, washing with methanol. The filtrate was concentrated in vacuo to give 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a brown solid (90%). (LC/MS (basic method): Rt 1.94, [M−H+]− 297. The product was used without any further purification.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10].CO.O>C(O)(CC)(C)C>[OH:15][CH2:14][CH:13]1[CH2:12][NH:11][C:9](=[O:10])[CH2:8][O:16]1
Reactant: O=C(CCl)NCC(O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)(C)O
Solvent: CO
Product: O=C1COC(CO)CN1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a stirred solution of potassium tert-butoxide (23.4 g, 299.4 mmol) in 200 mL tert-amyl alcohol at room temperature was added 2-chloro-N-(2,3-dihydroxypropyl) acetamide (Step-1 of Intermediate-9) (20 g, 119.6 mmol) in 460 mL tert-amyl alcohol for 2 h under nitrogen atmosphere. After one hour, MeOH (100 mL) and H2O (3 mL) were added and further stirred for 20 min. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel with MeOH/EtOAc (20:80) to give the title compound as a white solid (14.4 g). m/z 132.1
Reaction SMILES: [CH3:1][C:2](=O)[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.[Cl-].[OH:25][NH3+:26].N1C=CC=CC=1>O>[N:26](=[C:2]([C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1)[CH3:1])[OH:25]
Reactant: [NH3+]O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: CC(=NO)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
A mixture of 5α-pregna-2,16-diene-11,20-dione (60 g), hydroxylammonium chloride (21 g) and anhydrous pyridine (240 ml) was left to stand at room temperature overnight before diluting with ice and water. The precipitate obtained was collected by filtration, washed with water and dried in vacuo at 80° (62 g.). Crystallisation from ethyl acetate afforded the title compound, m.p. 168°-182°, [α]D +137°.
Reaction SMILES: CC1C=[C:12]2[O:14]C=1C[C@H:5]([C:21](C)=C)[CH2:6][CH2:7][C:8]1C(=O)O[C@@H:10]([C@H:11]2C(C)=C)[CH:9]=1.[C:24]([O:28][C:29](=[O:42])[N:30]([C@H]1CC[C@H](C=C(Br)Br)CC1)[CH3:31])([CH3:27])([CH3:26])[CH3:25].[Li]CCCC.C=O>C1COCC1>[C:24]([O:28][C:29](=[O:42])[N:30]([C@H:6]1[CH2:5][CH2:21][C@H:9]([C:10]#[C:11][CH2:12][OH:14])[CH2:8][CH2:7]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25]
Reactant: C=C(C)[C@@H]1CCC2=C[C@@H](OC2=O)[C@@H](C(=C)C)c2cc(C)c(o2)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 25 °C

Procedure:
The following reaction was performed in analogy to the reaction described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (−)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729–5735 and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415–21.). A solution of 993 mg (2.5 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 20 ml THF was treated at −78° C. with 3.28 ml (5.25 mmol) of BuLi (ca 1.6 M in hexane). After 2 h at this temperature 790 mg (25 mmol) of paraformaldehyde were added. The reaction mixture was warmed up to RT for 3 h and after 1 h at this temperature extracted with water/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 4:1) yielded 530 mg (79%) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 268 (MH+).
Reaction SMILES: C1(C(=[N:14][C@@H:15]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[C:16]([O:18]C(C)(C)C)=[O:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:35]>>[ClH:35].[NH2:14][C@@H:15]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=1)[C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Yield: 60 %

Procedure:
A 6 N hydrochloric acid (400 mL) solution of tert-butyl (2S)-2-[(diphenylmethylene)amino]-3-[4-(trifluoromethoxy)phenyl]propanoate (41.2 g, 87.7 mmol) prepared in Reference Example 3 (3a) was heated under reflux for 3 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure. The residue was washed with diethyl ether to give 23.8 g of a crude crystal (white powder, yield: 95%, optical purity: 84%). The crude crystalline solid (200 mg) was recrystallized from 1 N hydrochloric acid (1.5 mL) to give 120 mg of the title compound (colorless crystal, yield: 60%). No R-isomer was recognized in this compound by HPLC analysis according to the method described in Reference Example 3 (3c), and thereby it was confirmed that the optical purity was 99% or higher.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)C.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[N:38]=[C:39]=[O:40]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[NH:38][C:39](=[O:40])[N:16]([CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:24][CH2:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: CCCCCCCNCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Solvent: ClCCl
Product: CCCCCCCN(CCOc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Nc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound obtained in Example 1, Step e (57.3 mg) in methylene chloride (4 ml) was added with 2,4-dimethoxyphenyl isocyanate (54 μl, Aldrich) and stirred for 1 hour. The reaction mixture was added with a polyamine resin (100 mg, prepared by the method described in J. Am. Chem. Soc., 119, 4874–4881, 1997), further stirred for 1 hour and filtered, and the filtrate was concentrated. The resulting residue was dissolved in ethanol (2 ml), added with 1 N aqueous sodium hydroxide (0.2 ml) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, added with 1 N hydrochloric acid (0.2 ml) and concentrated. The resulting residue was dissolved in methylene chloride and washed with 1 N hydrochloric acid. The solution was dried and concentrated, and the resulting residue was applied on a silica gel column and eluted with hexane/acetone (2:1, containing 0.1% acetic acid) to obtain the title compound (59 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:27])=[O:26]
Reactant: Oc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
10.00 g (0.077 mol) of 2,4-difluorophenol, 100 mL of toluene and 8.17 g (0.081 mol) of triethylamine were mixed at 25° C., and with controlling the temperature of the reaction liquid to be at 20° C. or lower in an ice bath, 9.24 g (0.081 mol) of methanesulfonyl chloride was dropwise added thereto, taking 15 minutes, and these were reacted with stirring at 25° C. for 1 hour. Water was added to the reaction liquid to separate the organic layer, and the organic layer was washed twice with saturated sodium bicarbonate water and once with water, then dried with anhydrous MgSO4 and subjected to distillation under reduced pressure (98° C./3 Torr) to give 15.1 g of 2,4-difluorophenyl methanesulfonate (yield 94%).