Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:7])([CH3:6])[CH2:4][NH2:5].[C:8](N1C=CN=C1)([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:9]>CN(C=O)C>[F:2][C:3]([F:7])([CH3:6])[CH2:4][NH:5][C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(F)(F)CN
Agent: Cl
Solvent: CN(C)C=O
Product: CC(F)(F)CNC(=O)n1ccnc1

Procedure:
TEA (1.3 mL, 0.8 mmol) was added to a solution of 2,2-difluoropropylamine hydrochloride (82 mg, 0.62 mmol) and 1,1′-CARBONYLDIIMIDAZOLE (114 mg, 0.7 mmol) in DMF (3 mL) (clear colorless solution). The solution was used for the synthesis of compound 5 without further isolation of compound 9.
Reaction SMILES: ClC1C=CC(CCC(C2C=CC=CN=2)=O)=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]/[C:27](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26]/[C:27](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:24]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1ccccn1
Agent: O=C(CCc1ccc(Cl)cc1)c1ccccn1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1ccccn1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-chlorophenyl)-1-(2-pyridinyl)propan-1-one, (Z)-ethyl 5-(4-chlorophenyl)-3-(2-pyridinyl)pent-2-enoate and (E)-ethyl 5-(4-chlorophenyl)-3-(2-pyridinyl)pent-2-enoate were obtained as colourless oils.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:16])[CH3:17])[N:13]=[C:12]([CH2:18][O:19][C:31](=[O:32])[NH2:33])[C:11]=2[CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)n1nc(CO)c(COCc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1nc(COC(N)=O)c(COCc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a solution of 120 mg of 5-(3,5-Dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methoxymethyl]-1H-pyrazole-3-methanol in 1 ml of dichloromethane at 0° C. was added 11 mg of trichloroacetyl isocyanate. The mixture was stirred for 2 h at 0° C. then the solvent was removed. The residue was dissolved in 2 ml of methanol and 1 ml of water, 100 mg of potassium carbonate added, and the mixture stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography using methanol/dichloromethane for the elution to give 12 mg of carbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methoxymethyl]-1H-pyrazol-3-yl]methyl ester as a white solid. Mass spectrum (ES) m/z 481 [M]+. 1H NMR (DMSO-d6) 1.25 (d, 6H), 4.50 (s, 2H), 4.52 (s, 2H), 4.80 (m, 1H), 5.05 (s, 2H), 6.55 (br s, 1H), 6.75 (br s, 1H), 7.08 (m, 2H), 7.16 (d, 2H) 7.45 (m, 1H), 8.43 (d, 2H).
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=C(C)C=C(C)C=1>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[NH:9][CH2:13]1
Reactant: NC(=O)c1sccc1S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1cc(C)cc(C)c1
Solvent: O
Product: O=C1NCSc2ccsc21

Procedure:
aad) 11.1 g of 3-mercapto-thiophene-2-carboxamide, 2.2 g of 95 percent paraformaldehyde and 13.3 g of p-toluenesulfonic acid monohydrate were heated together under reflux with 300 ml of mesitylene. After the reaction finished, the mixture was left to cool and the solvent was removed in vacuo. After chromatography of the residue on silica gel and recrystallization from ethyl acetate, there was obtained 2,3-dihydro-4H-thieno[2,3-e][1,3]thiazin-4-one as yellowish crystals of m.p. 153°-155°.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[C:24]([Br:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18](Cl)=[O:19].[Cl-].[NH4+]>C1COCC1>[Cl:15][C:16]1[C:24]([Br:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18]([C:4]([CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:19]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc(Br)c1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(=O)OCC)C(=O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.2 g of 55% sodium hydride was suspended in 30 ml of THF, followed by the addition of 50 ml of a THF solution of 8.65 ml (50.3 mmol) of diethyl methylmalonate under cooling with ice. The obtained mixture was stirred at room temperature for 20 minutes and cooled with ice again, followed by the dropwise addition of 85 ml of a THF solution of the 2-chloro-3-bromo-5-nitrobenzoyl chloride prepared in the above Example. The obtained mixture was stirred as such for 1.5 hours and then poured into an aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated brine, dried and distilled to remove the solvent. 30 ml of methylene chloride was added to the residue. The resulting mixture was freed from insolubles by filtration and concentrated under reduced pressure to give 21.77 g of the title compound (yield: quantitative).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:20]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1Cl
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(F)c(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2,3-dichloro-4-fluorobenzenesulphonyl chloride (Example 185a) (0.31 g). Yield 0.042 g.
Reaction SMILES: C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:23]([NH:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([OH:47])=O)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH:57][C:45]([C:44]1[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=1[NH:42][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:47]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)O
Reactant: CN(C)CCCN
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.44 ml) and diphenylphosphinic chloride (0.48 ml) were added to a suspension of 2-(octadecanoylamino)benzoic acid (0.85 g) in methylene chloride (10 ml). After being stirred for 3 hours at 0° C., the mixture, with N,N-dimethyl-1,3-propanediamine (0.33 ml) added thereto, was stirred for 44 hours at room temperature. The reaction mixture was then diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 20 g, chloroform-methanol), thereby yielding 0.53 g of N-{2-{N-{3-(dimethylamino)propyl}carbamoyl}phenyl}octadecaneamide and 0.37 g of the aimed compound as colorless crystals.
Reaction SMILES: COC1C=CC(N=[N:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:12]=2[OH:40])=CC=1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:12]=1[OH:40]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc2ccccc2c(N=Nc2ccc(OC)cc2)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1cc2ccccc2c(N)c1O

Procedure:
To a mixture of 17 g (0.031 mole) 1-(p-methoxyphenylazo)-3-octadecyloxy-2-naphthol and 700 ml ethanol was added a solution 13.5 g (0.070 mole) sodium dithionite in 80 ml water. The mixture was refluxed for 2.5 hours, cooled, and filtered. The while solid, 11 g, was recrystallized from a mixture of hexane and ethyl acetate to give an off-white solid, m.p. 97°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH:12]=[O:13])=[CH:6][CH:5]=1)[CH3:2].[CH2:15]([Mg]Br)[CH3:16]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH:12]([OH:13])[CH2:15][CH3:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=C(C)C=O)cc1
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCOc1ccc(C=C(C)C(O)CC)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-ethoxyphenyl)-2-methylpropenaldehyde (10 g, 0.053 mol) in dried diethyl ether (150 ml) cooled to −15° C. and stirred under an atmosphere of nitrogen was added a solution of ethylmagnesium bromide in diethylether (3M, 19.3 ml) The reaction mixture was allowed to warm to room temperature and after ½ h poured onto ice cold aqueous hydrochloric acid (2M, 50 ml) and the organic phase washed with water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to give 1-(4-ethoxyphenyl)-3-hydroxy-2-methylpent-1-ene as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][C:17]([F:20])([F:19])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of commercially available 4-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.561 g; 19.70 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 1 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 4-(2,2,2-trifluoroethoxy)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.72 min.; no ionisation.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:22]2=[O:28])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.Cl>ClCCl>[O:28]=[C:22]1[CH:21]([N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])=[CH:3][CH:4]=2)[S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1
Reactant: Nc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1)C1CC1
Yield: 14 %

Procedure:
Rac-4-trifluoromethyl-benzenesulfonic acid (4-amino-benzyl)-(2-oxo-azepan-3-yl)-amide (75 mg, 0.17 mmol) is dissolved in dichloromethane (2 ml), then pyridine (80 mg, 1 mmol) and cyclopropanecarbonyl chloride (21 mg, 0.2 mmol) were added. After shaking the mixture at room temperature for 1 hour hydrochloric acid (5 ml, 0.1M) was added. The organic layer was separated evaporated and the residue was redissolved in 1 ml of dimethylformamide for preparative HPLC separation (RP—C18, eluent acetonitrile/water) to yield 12 mg (14% of the final product). MS: m/e=510.4 (MH+), 527.2 (M+NH4+).
Reaction SMILES: OS(O)(=O)=O.[OH:6][CH2:7][C:8]([CH2:13][OH:14])([CH3:12])[C:9]([OH:11])=[O:10].[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[C:8]([CH2:13][OH:14])([CH3:12])[CH2:7][OH:6]
Reactant: CC(CO)(CO)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Add H2SO4 (4.5 g) to a suspension of 3-Hydroxy-2-hydroxymethyl-2-methyl-propionic acid (100 g) in MeOH (1 L, HPLC grade solvent) and stir at room temperature. for about 70 hours. Remove the solvent and partition the residue between EtOAc (1 L) and H2O (100 mL). Re-extract the aqueous layer with EtOAc, and dry the combined organic fractions over MgSO4. Filter and concentrate under reduced pressure. Crude mixture can be used without further purification. 1H NMR (CDCl3, 300 MHz): δ ppm 3.9 (d, 2H, J=11.1 Hz), 3.76 (s, 3H), 3.71 (d, 2H, J=11.1 Hz), 2.8 (bs, 2H), 1.1 (s, 3H)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (80 mg, 245 μmol), 6-chloronicotinonitrile (50 mg, 368 μmol) and anhydrous K2CO3 (102 mg, 735 μmol) in DMF (2 mL) was heated at 100° C. overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine and then dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 429 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17](Cl)=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1.[CH2:23]([CH:26]([NH2:30])[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([NH:30][CH:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1
Reactant: CCCC(N)CCC
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (30.0 g), 1-propyl-butylamine (18.5 g), N,N-diisopropylethylamine (15.5 g) in ethanol (90 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with diisopropylether to give 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (27.0 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[C:27]([Si:31]([O:34][CH2:35][CH:36]1[CH2:38][CH:37]1[CH2:39][CH2:40]Br)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[Si:31]([O:34][CH2:35][CH:36]1[CH2:38][CH:37]1[CH2:39][CH2:40][C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC1CCBr
Reactant: C#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
A tetrahydrofuran solution (15 ml) of propargyl alcohol tetrahydropyranyl ether (1.44 g, 10.3 mmol) was cooled to -78° C., and butyllithium (factor=1.5, 6.9 ml, 10.3 mmol) was added thereto. Fifteen minutes later, the temperature was raised to 0° C. Hexamethylphosphoric triamide (3.76 ml, 21 mmol) was added thereto, and the mixture was stirred for 15 minutes. A tetrahydrofuran solution of 2-(2-bromoethyl)cyclopropylmethyl t-butyldimethyl silyl ether (2.73 g, 10.3 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added thereto, and the product was extracted with ethyl ether. The crude product was purified by silica gel column chromatography to obtain 2-(5-tetrahydropyranyloxy-3-pentynyl)cyclopropylmethyl t-butyldimethylsilyl ether (3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O.C(O)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>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccncc2)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccncc2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
trans-Dichlorobis (triphenylphosphine)palladium (II) (0.050 g, 0.07 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-pyridin-4-ylsulfonylpropan-2-yl)pyrimidine (0.560 g, 1.41 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.464 g, 2.12 mmol) and sodium carbonate (3.53 mL, 7.05 mmol) in 18% DMF in a mixture of DME:water:ethanol (7:3:2) (30 mL) at RT under nitrogen. The resulting solution was stirred at 80° C. for 5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice and the combined organics dried (MgSO4), filtered and evaporated to afford the desired material (0.640 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:59]1[N:64]=[CH:63][CH:62]=[CH:61][N:60]=1)CCC.O>CN1CCCC1=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:59]3[N:64]=[CH:63][CH:62]=[CH:61][N:60]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(-c2ncccn2)s1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A mixed solution of the above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene 53 (200 mg), tri-n-butyl(2-pyrimidinyl)tin 54 (137 mg) and bis(triphenylphosphine)palladium(II)dichloride (9 mg) in N-methyl-2-pyrrolidinone (5 ml) was stirred at 100° C. four 7 hours under argon atmosphere. The mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and subsequently with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene 55 (93 mg) as pale brown oil. APCI-Mass m/Z 826/828 (M+NH4).
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.CCCC1C2C3OC(C)(C)C=CC=3C3O[C@@H](C)[C@H](C)[C@@H](O)C=3C=2OC(=O)C=1.CCCCCC.C(OCC)(=O)C>CCCCCC.C(O)C>[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][CH:17]([CH3:19])[CH:16]([CH3:20])[CH: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
Agent: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O

Procedure:
The synthetic ±-1 was resolved into enantiomers, (+)-calanolide A and (−)-calanolide A, by preparative HPLC16. Thus, using a normal phase silica gel HPLC column (250 mm×4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analytical, Inc., PA, USA), the synthetic (±)-1 appeared as one peak with a retention time of 10.15 minutes when hexane/ethyl acetate (70:30) was used as the mobile phase at a flow rate of 1.5 mL/min and a wavelength of 290 nm was used as the uv detector setting. However, on a chiral HPLC column packed with amylose carbamate (250 mm×4.6 mm I.D. Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., PA, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1:1 were observed at a flow rate of 1.5 mL/min. The mobile phase was hexane/ethanol (95:5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral HPLC column, providing the pure enantiomers of calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the reported natural product, were characterized by spectroscopic data. HPLC chromatograms of (+)-calanolide A and its optical forms are shown in FIG. 6.