Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[C:4]1/[C:5](=O)[C:6]2[S:10][C:9]([N:11]=CN(C)C)=[N:8][C:7]=2[CH2:16][CH2:17]/1.[OH-].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25]([NH2:27])=[NH:26])[CH3:23]>COCCO>[NH2:11][C:9]1[S:10][C:6]2[C:5]3[N:27]=[C:25]([N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])[N:26]=[CH:3][C:4]=3[CH2:17][CH2:16][C:7]=2[N:8]=1
Reactant: CN(C)C=Nc1nc2c(s1)C(=O)/C(=C/N(C)C)CC2
Reactant: CCN(CC)C(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCN(CC)c1ncc2c(n1)-c1sc(N)nc1CC2
Temperature: 125 °C
Reaction time: 3.5 h

Procedure:
To N′-{6-[1-dimethylamino-meth-(E)-ylidene]-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl}-N,N-dimethyl-formamidine (Stage A.2, 1 g, 3.59 mmol) in 2-methoxyethanol (10 mL) was added NaOH (0.539 g, 13.47 mmol) and N,N-diethylguanidine (0.454 g, 3.94 mmol) under argon at rt. The RM was stirred for 3.5 h at 125° C. and then cooled to rt. After evaporation in vacuo the residue was dissolved in 0.1 M HCl (50 mL) and washed with EtOAc. The aqueous layer was then basified with 6 N NaOH and extracted 3× with EtOAc. the organic layers were dried over Na2SO4, evaporated and dried under high vacuum at 60° C. to give the title compound as orange crystals. LC: tR 3.60 min (method D). MS: M+H=276. 1H-NMR in DMSO-d6: 7.91 (s, 1H); 7.59 (s, 2H); 3.50 (q, 4H); 2.69 (dd, 4H); 1.07 (t, 6H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:21](O)=[O:22])=[CH:15][CH:16]=2)[CH:11]=[N:10][N:9]=1>>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:21]([O:5][CH2:1][CH3:2])=[O:22])=[CH:15][CH:16]=2)[CH:11]=[N:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a 250 mL dry flask containing anhydrous ethanol (50 mL) stirred at 0° C. was added dropwise oxalyl chloride (54 mmol). After 5 minutes 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoic acid (18 mmol) was added in one portion, the suspension was warmed up to reflux and stirred for 3 h. The solvent was evaporated and the residue was vacuum dried at RT for about 2 h to give ethyl 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoate 5.5 g as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.6 g, 4.6 mmol) in DCM (90 mL) was added m-CPBA (1.0 g, 5.8 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na2S2O3 (45 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole as a yellow solid (1.68 g, 100%). 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 1H), 7.92 (d, J=3.6 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.53 (dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15](OS(C)(=O)=O)[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)C(C)CN(c1c(C)cccc1C)S(C)(=O)=O
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 15 g (45 mmoles) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-methanesulfonyloxy-propane and 45 ml (31.9 g, 0.44 moles) of diethyl amine is heated at 150° C. for 5 hours in a steel bomb. The mixture is cooled, dissolved in 300 ml of diethyl ether, the solution is washed thrice with 50 ml of water, each, and then extracted thrice with 70 ml of ice-cold 1 n hydrochloric acid, each. The acidic solutions are combined, the traces of diethyl ether are removed under reduced pressure, and then the pH of the solution is adjusted to 9 with concentrated aqueous ammonia. The mixture is allowed to stand at +5° C. for one hour. The separated crystalline substance is filtered off, washed with water and dried. 8.3 g (59.1%) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-diethylamino-propane are obtained as a light beige, crystalline substance; m.p.: 58°-60° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH:30]1[CH2:33][CH:32]([OH:34])[CH2:31]1.C(O)C>C1COCC1>[ClH:1].[OH:34][CH:32]1[CH2:33][N:30]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:31]1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: OC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CC(O)C2)ncn1
Reaction time: 1 h

Procedure:
100 mg (0.4 mmol) of the compound from Example 23, 94 mg (0.7 mmol) of N,N-diisopropylethylamine and 80 mg (0.7 mmol) of azetidin-3-ol hydrochloride are suspended in 3 ml of THF and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 20 min. 2 ml of ethanol are then added, and the mixture is again reacted in a single-mode microwave oven (CEM Explorer) for 20 min. The mixture is then reacted initially at 120° C. for a further 60 min and then at 175° C. for 60 min in a single-mode microwave oven (CEM Explorer). The mixture is then separated directly by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated on a rotary evaporator, and the residue is dried under high vacuum. The residue is then stirred in 5 ml of a 4 N solution of hydrogen chloride in dioxane for 30 min. The solid is filtered off, washed with tert-butyl methyl ether and dried under high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[F:24][C:25]([F:64])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:44]=3B3OC(C)(C)C(C)(C)O3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:64][C:25]([F:24])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:46]=[CH:45][C:44]=3[C:5]3[C:6]([O:8][CH3:9])=[CH:7][C:2]([F:1])=[C:3]([CH:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH:4]=3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1
Reactant: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1I
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of tert-butyl 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine-1-carboxylate (58 mg; 0.133 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (111 mg, 0.187 mmol) was treated with 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (˜10 mg) as described earlier. The product was purified by chiral HPLC (ChiralPak OD column, 10% IPA/heptane) to afford tert-butyl 4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidine-1-carboxylate as a colorless glass. LCMS=678.8 (M+1-100)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.86 (s, 1 H), 7.69 (s, 2 H), 7.64-7.61 (m, 2 H), 7.32 (d, J=8 Hz, 1 H), 6.96 (d, J=8.4 Hz, 1 H), 6.70 (d, J=11.9 Hz, 1 H), 5.57 (d, J=8 Hz, 1 H), 4.88 (d, J=15.8 Hz, 1 H), 4.26-4.17 (m, 2 H), 3.86 (d, J=15.8 Hz, 1H), 3.83-3.78 (m, 1 H), 3.77 (s, 3 H), 3.01-2.93 (m, 1 H), 2.84-2.75 (m, 2 H), 1.84-1.69 (m, 2 H), 1.64-1.50 (m, 2 H), 1.45 (s, 9H), 0.38 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19]#[N:20])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].[ClH:23].C[OH:25]>>[ClH:23].[ClH:23].[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19](=[O:25])[NH2:20])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: CO
Reactant: CNC(=NC#N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: Cl
Product: CNC(=NC(N)=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[5-(2-cyano-3-methylguanidino)methylfuran-2-yl]thiazole (2.28 g) and 4M-dioxanic hydrogen chloride (10 ml) in methanol (20 ml) was stirred at ambient temperature for 19 hours and further at 50° C. for 5 hours. The resulting precipitate was collected by filtration, washed with methanol, and recrystallized from a mixture of methanol and water to afford 2-(diaminomethyleneamino)-4-[5-(2-carbamoyl-3-methylguanidino)methylfuran-2-yl]thiazole dihydrochloride (1.65 g).
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].[CH:8]([CH:10]([CH2:15][C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[C:11](OC)=O)=[O:9]>C(O)C>[CH3:21][N:19]1[CH:20]=[C:16]([CH2:15][C:10]2[C:8](=[O:9])[N:6]=[C:5]([NH:4][N+:1]([O-:3])=[O:2])[NH:7][CH:11]=2)[CH:17]=[N:18]1
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Solvent: CCO
Product: Cn1cc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To the solution of N-nitroguanidine (912 mg, 8.76 mmol) in ethanol (50.0 mL) was added methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (858 mg, 4.38 mmol). It was stirred at 70° C. overnight. After removing the solvent, 10 mL water was added. Then HCl(conc) was added to adjust pH ˜3, and the solution was stirred at 0° C. for 1 h. The solid was collected after filtration. It was dried overnight at 50° C. to get the title compound as an off-white solid (674 mg, 61.5% yield). LCMS: rt=1.17 min, [M+H+]=251.1
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.[P:14]([O-:26])([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:16][CH3:17])=[O:15].[K+].CC(C)=O>CCOCC>[P:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:16][CH3:17])([O:26][CH2:10][C:9]([NH:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:13])=[CH:5][CH:6]=1)=[O:12])=[O:15]
Reactant: COP(=O)([O-])Oc1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)CCl)c(C)n1
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COP(=O)(OCC(=O)Nc1ccc(C)nc1C)Oc1ccc(Cl)cc1

Procedure:
N-(2,6-Dimethyl-3-pyridyl)-α-chloroacetamide (32.2 grams), potassium O-methyl O-(4-chlorophenyl) phosphate (26 grams) and acetone (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 24 hours. After this time the mixture is stripped of solvent on a steam bath and the resulting residue is dissolved in ether. The ether solution is washed with water and is dried over magnesium sulfate. The dried solution is then evaporated under vacuum to yield the desired product O-[2-(2,6-dimethyl-3-pyridylamino)-2-ketoethyl] O-methyl O-(4-chlorophenyl) phosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:25]([CH3:24])(=[O:27])=[O:26])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(Cl)ccc1NCc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(Cl)ccc1N(Cc1cccnc1)S(C)(=O)=O

Procedure:
A 2.5 g. portion of 3-(4-chloro-2-methoxyphenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane, and to it were added 2.1 g. of potassium carbonate and 1.2 ml. of methanesulfonyl chloride. The mixture was stirred with gentle heating for 2 days, and was then extracted with aqueous sodium bicarbonate. The organic phase was dried and evaporated under vacuum, and the residue was redissolved in dichloromethane and 2.6 g. of methanesulfonic anhydride was added. The mixture was stirred at ambient temperature for several days, and another 2.6 g. of the anhydride was added, together with 2.5 g. of additional starting amine. The mixture was stirred at ambient temperature for several days more, and was then diluted with 20 ml. of aqueous sodium bicarbonate and 15 ml. of dichloromethane, and the organic phase was dried over magnesium sulfate and evaporated to an oil. The oil was taken up in chloroform and chromatographed over silica gel, eluting with chloroform, to obtain 1.17 g. of the desired compound, m.p. 121°-123°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH3:12][C:13]1[S:14][CH:15]=[N:16][N:17]=1>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[CH:12][C:13]1[S:14][CH:15]=[N:16][N:17]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: Cc1nncs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nncs1

Procedure:
0.3 g of zinc chloride is added to 15.5 g of 1-methyl-5nitroimidazol-2-carboxaldehyde which has been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride and the whole is dripped into 10 g of 2-methyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride, over a period of 5 hours at reflux temperature. After 24 hours the reaction mixture is freed of the solvent by evaporation and ether is added. After the reaction product has been washed with water it is recrystallized from xylene. 9.3 of product, corresponding to 39% of the theory, is obtained. The compound melts at 214° C.
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].[CH:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=1)([CH3:9])[CH3:8].P(Cl)(Cl)(Cl)=O.[OH-].[K+]>O>[C:2]([C:13]1[C:12]2[C:16]([CH:17]=[CH:18][CH:19]=[C:10]([CH:7]([CH3:9])[CH3:8])[CH:11]=2)=[CH:15][CH:14]=1)(=[O:3])[CH3:1]
Reactant: CC(C)c1cccc2cccc-2c1
Reactant: CC(=O)N(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc2cccc(C(C)C)cc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a dimethylacetamide (80 ml) solution of the compound (19) (8.41 g), while stirring and cooling with ice. a dimethylacetamide (76 ml) solution of phosphorus oxychloride (POC13) (92 g) was added dropwise over 40 minutes. After the addition of the POC13 solution, it was further stirred for 5 hours at room temperature, and then poured into water (800 ml). The solution was made basic (pH 10) by the addition of aqueous potassium hydroxide, and was extracted 5 times with benzene. The benzene solutions were mixed, washed with water and dried. From the benzene solution, the solvent was distilled off to obtain an oily substance. It was purified by silica gel column chromatography (650 g), eluting with benzene. The secondeluted part gave 1-acetyl-7-isopropylazulene (20) (4.29 g, 41%) in a red oily state.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C@H:14]2[C@H:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:18]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:17]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:15]2)[CH:13]=1)[CH:9]=[O:10].CO.C1COCC1>O.CC(C)=O>[CH2:21]([O:20][C@@H:19]1[C@@H:18]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:15][C@H:14]1[C:12]1[CH:13]=[C:6]([CH2:5][O:4][CH3:3])[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCc1cc(C=O)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(CO)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Sodium borohydride (0.15 g) was added to a solution of 3-methoxymethyl-5-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzaldehyde (2.6 g) in a 1:1 mixture of methanol and THF (10 ml) and the mixture was stirred for one hour. Acetone (5.0 ml) was added to the reaction mixture and the mixture was stirred for 10 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(hydroxymethyl)-5-(methoxymethyl) phenyl]-D-glucitol (2.1 g).
Reaction SMILES: [CH2:1]([Mg]I)[CH3:2].[Mg].C(I)C.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([F:18])[CH:11]=1>C(OCC)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH3:2])=[C:12]([F:18])[CH:11]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC[Mg]I
Agent: [Mg]
Solvent: CCI
Solvent: CCOCC
Product: CCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a ice-cold solution of ethyl magnesium iodide prepared from magnesium (2.39 g, 98.51 mmoles) and ethyl iodide (7.88 ml, 98.51 mmoles) in diethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmoles) in diethyl ether (10 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5.8 g, 99% yield) which is used as such for step.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([O:4][C:5]([NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:6])[CH3:3]>C(O)(C)C.[Rh]>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][CH:8]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:9]([OH:16])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:6])[CH3:24]
Reactant: CC(C)OC(=O)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CC(C)O
Product: CC(C)OC(=O)C(O)C(CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 85 %

Procedure:
To β-[[(1,1-dimethylethoxy)carbonyl]amino]-α-hydroxybenzenebutanoic acid, 1-methylethyl ester (mixture of R-(R*,S*)] and [S-(R*,R*)]isomers) (Example E), 4.2 g (12.4 mmol), in isopropanol (100 ml) is added 10% rhodium on carbon, 1.0 g, and the mixture is stirred under a hydrogen atmosphere for 16 hours. The solution is filtered and evaporated in vacuo to give a 3.6 g (85%) of the title compound as a tan oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])=[O:3]
Reactant: CC(=O)Nc1ccccc1C(C)=O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 g (0.175 mol) of N-(2-acetylphenyl)acetamide (prepared by acylating 2-aminoacetophenone with acetyl chloride according to Fuerstner, Alois; Jumbam, Denis N.; Tetrahedron; 48; 29; 5991-6010, (1992)) were dissolved in 200 ml of glacial acetic acid. 127 ml of 33% HBr in glacial acetic acid were added and then 8.75 ml (0.175 mol) of bromine were added slowly at room temperature. The mixture was stirred at room temperature overnight. The mixture was stirred into 1.5 l of ice-water, and the precipitated product was filtered off with suction, washed thoroughly with ice-water and dried in vacuo. According to HPLC and NMR, the crude product contained some reactant and dibrominated product, but was clean enough for the further reaction (approx. 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
5-bromo-2-chloronicotinic acid (8.157 g, 34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.94 g, 36 mmol) were dissolved in DCM (200 ml) and triethylamine (5.3 ml, 38 mmol) and aniline (3.5 ml, 38 mmol) were added. The reaction was stirred under nitrogen overnight at room temperature. More aniline (1.5 ml, 16 mmol) was added the next morning and stirring was continued. When LCMS analysis indicated the formation of the product, the reaction was quenched with water (150 ml). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were washed with 1N HCl (2×50 ml), saturated sodium bicarbonate (50 ml), and brine (50 ml). They were then combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (˜3 inches, 50:1→30:1 DCM/MeOH). To afford the desired 5-bromo-2-chloro-N-phenylnicotinamide (2.85 g, 9.15 mmol, 26%). MS (ESI pos. ion) m/z: 311 (MH+, 79Br), 313 (MH+, 81Br). Calc'd exact mass for C12H8BrClN2O: 310 (79Br), 312 (81Br).