Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=2)=[CH:19][CH:18]=1>ClCCl.CN(C)C=O>[N:29]([C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=2)[N:28]=[CH:27][N:26]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(-c2ccncc2)ncn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C=Nc1cc(-c2ccncc2)ncn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.601 g, 2.59 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(pyridin-4-yl)pyrimidin-4-amine (0.297 g, 1.725 mmol). The orange mixture was heated at 60° C. for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257 mmol, 15% yield) as an orange solid. LCMS R.T.=1.46; [M+H]+=215.09.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[N:33]4[C:28]([CH:29]=[N:30][C:31](S(C)=O)=[N:32]4)=[CH:27][CH:26]=3)[C:19]=2[O:18][CH2:17][CH2:16]1.C([O-])(=O)C.[K+].CS(C)=O>>[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[N:33]4[C:28]([CH:29]=[N:30][C:31]([NH:14][C:11]5[CH:12]=[CH:13][C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:9][CH:10]=5)=[N:32]4)=[CH:27][CH:26]=3)[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CS(=O)c1ncc2ccc(-c3cccc4c3OCCO4)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc6c5OCCO6)n4n3)cc2)CC1
Temperature: 140 °C
Yield: 64.4 %

Procedure:
A mixture of 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.086 g, 0.45 mmol), 7-(2,3-Dihydro-1,4-benzodioxin-5-yl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.08 g, 0.20 mmol) and Potassium acetate (0.12 g, 1.2 mmol) in Dimethyl sulfoxide (0.9 mL, 10 mmol) was heated in sealed tube at 140° C. for 4 hours. Dilution of the mixture with water (20 mL) and extraction with DCM, gave a brown solid. Purification by prep plate chromatography with DCM-methanol (10-1) gave [7-(2,3-Dihydro-1,4-benzodioxin-5-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.057 g, 50%). MP: 212-213° C.; LCMS (m/e) 443 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.16 (s, 1H), 8.91 (s, 1H), 7.60-7.58 (d, 2H, J=9.00 Hz), 7.44-7.42 (dd, 1H, J=4.97 Hz), 7.02-6.96 (q, 2H, J=8.04 Hz), 6.93-6.92 (d, 1H, J=4.65 Hz), 6.88-6.87 (d, 1H, J=4.64 Hz), 6.81-6.79 (d, 2H, J=9.01 Hz), 5.76 (s, 1H), 4.30-4.25 (d, 4H, J=4.88 Hz), 3.32 (s, 3H), 3.03 (s, 3H), 2.45-2.43 (t, 1H, J=4.76 Hz), 2.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24]Br)=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:26].BrCC1C=CC2C(=CC=CC=2)C=1>>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][O:12][CH2:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]([CH3:13])[C:15](=[O:26])[CH:16]=[CH:17]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#CCO)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Agent: BrCc1ccc2ccccc2c1
Product: COC1(/C=C/COCc2ccc3c(ccc(=O)n3C)c2)CCOCC1

Procedure:
The desired compound was prepared according to the method of Example 1, step 4, except substituting 4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as in Example 3, for 4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran, and substituting 1,2-dihydro-1-methyl-2-oxo-6-(bromomethyl)quinoline for 2-(bromomethyl)naphthalene. 1H NMR (300 MHz, CDCl3); 7.67 (1H, d, J=9 Hz), 7.52-7.58 (2H, m), 7.35 (1H, d, J=9 Hz), 6.72 (1H, d, J=9 Hz), 5.75 (1H, dt, J=15.5,8 Hz), 5.63 (1H, br d, J=16 Hz), 4.60 (2H, s), 4.10 (2H, dd, J=8,1 Hz), 3.67-3.8 (4H, m), 3.15 (3H, s), 1.72-1.77 (4H, m); MS (M+H)+ =344. Analysis calc'd for C20H25NO4 : C, 69.95; H, 7.34; N, 4.08; Found: C, 69.68; H, 7.16; N, 3.99
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[OH-].[NH4+:11]>C1C=CC=CC=1>[CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH2:11])=[O:8])[CH:3]=1
Reactant: Cc1cc(C(=O)Cl)co1
Reactant: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1cc(C(N)=O)co1
Reaction time: 3 h

Procedure:
24.7 g (171 mmol) of 5-methylfuran-3-carbonyl chloride were added dropwise to a stirred mixture of 80 ml of a 25% strength ammonium hydroxide solution and 80 ml of benzene at 25-40° C. The resulting mixture was stirred for 3 h and left to stand overnight. The next day, white crystals of the amide were filtered off, washed with cold water and dried to constant weight at 40-45° C. Yield 19.7 g (158 mmol, 92%), melting point 158° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](N(CC)CC)C.CI>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][CH3:31])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: CI
Solvent: ClCCl
Product: CNc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1

Procedure:
2-[4-(4-amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5050, 38 mg, 0.092 mmol) was dissolved in 3.5 mL of methylene chloride. To this solution was added triethylamine (12.8 μL, 0.092 mmol) followed by 6 μL (0.092 mmol) of methyl iodide. This solution was heated under reflux for 1 hour. It was evaporated and redissolved in 5 mL of DMF. The crude was purified using reverse phase HPLC to furnish the desired product. MS: 437.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[O:10][C:9]2[C:11]([NH:15][C:16](=[O:30])[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=3)=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1.[NH3:32]>C(O)C>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:18]=[CH:17][C:16]([NH:15][C:11]2[C:9]3[O:10][CH:5]([CH2:4][C:3]([NH2:32])=[O:2])[CH2:6][O:7][C:8]=3[CH:14]=[CH:13][CH:12]=2)=[O:30])=[CH:20][CH:21]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: N
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1
Solvent: CCO
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(N)=O)CO3)cc1
Reaction time: 72 h

Procedure:
8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetic acid methyl ester (341 mg; synthesized in reference example 3) was dissolved into ethanol which was saturated with ammonia (20 ml). The solution was allowed to stand for 3 days at 100° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (191 mg).
Reaction SMILES: [S:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C1(C)C=CC=CC=1>O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:7](=[O:9])[CH:6]3[S:1][CH:2]([CH2:3][CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:18][CH2:19]1
Reactant: O=C1OC(=O)C2CCCC1S2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C2CCCC(S2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
Tetrahydrothiopyran-2,6-dicarboxylic anhydride (2.4 g., 14 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (3.5 g., 15 mmole) were dissolved in 250 ml. of toluene and refluxed for 48 hours with water removal via a Dean-Shark trap. The solvent was removed in vacuum and replaced with chloroform. The mixture was filtered through 75 g. of silica gel and concentrated in vacuum and the residue was crystallized from isopropanol with addition of 4N isopropanolic HCl. A second crystallization from isopropanol gave 1. g. of the title compound as the monohydrochloride; m.p. 238°-241° C. (d).
Reaction SMILES: C[C:2]1[C:16]([C:17](O)=[O:18])=[CH:15][C:5]2[N:6]([CH3:14])[C:7]([CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.Cl.[CH3:28][C:29]1[N:33]=[C:32]([C@H:34]([NH2:36])[CH3:35])[O:31][N:30]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:3]2[C:4]3[N:8]=[C:7]([CH2:9][C:10]([OH:13])([CH3:11])[CH3:12])[N:6]([CH3:14])[C:5]=3[CH:15]=[C:16]([C:17]([NH:36][C@@H:34]([C:32]3[O:31][N:30]=[C:29]([CH3:28])[N:33]=3)[CH3:35])=[O:18])[CH:2]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(C(=O)O)cc2c(nc(CC(C)(C)O)n2C)c1-c1ccc(F)cc1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3nc(CC(C)(C)O)n(C)c3c2)n1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a mixture of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1-methyl-1H-benzimidazole-6-carboxylic acid (122 mg, 0.236 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (46.3 mg, 0.283 mmol), 1-hydroxy-7-azabenzotriazol (3.21 mg, 0.024 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (79 mg, 0.412 mmol) was added DMF (0.471 mL) followed by triethylamine (0.099 mL, 0.707 mmol). Reaction heated at 50° C. for 30 min. Reaction cooled and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (87.4 mg): LC-MS [M+1]=452.4; 1H NMR (500 MHz, CHCl3-d): δ 7.94 (2H, m), 7.90 (1H, s), 7.77 (1H, s), 7.20 (1H, d, J=7.73 Hz), 7.15 (2H, t, J=8.51 Hz), 5.66-5.59 (1H, m), 5.47 (1H, s), 3.78 (3H, s), 3.02 (2H, s), 2.39 (3H, s), 1.74 (5H, d, J=7.14 Hz), 1.35 (6H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:20][N:21]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
6 g (0.024 mole) of 4-(4-(2-methoxy-ethoxy)-phenyl)-4-oxo-butyric acid and 1.2 g (0.024 mole) of hydrazine hydrate are stirred in 90 ml of ethanol at 50° C. for 1 hour. After the mixture has been cooled, the product is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:12]2[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:11]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(F)cc2)c1)C(=O)OC(C)(C)C

Procedure:
By an operation similar to that in Reference Example 32 and using tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (305 mg), and 4-fluorobenzenesulfonyl chloride (292 mg), the title compound was obtained as a colorless oil (yield 436 mg, 94%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=2)[NH:8][C:7]=1[C:19]([F:22])([F:21])[F:20])C.[NH3:24]>CO>[CH3:17][N:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:19]([F:22])([F:21])[F:20])=[C:6]2[CH2:5][C:4]([NH2:24])=[O:3])[CH3:18]
Reactant: N
Reactant: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(CN(C)C)cc12
Solvent: CO
Product: CN(C)Cc1ccc2[nH]c(C(F)(F)F)c(CC(N)=O)c2c1
Temperature: 80 °C
Reaction time: 144 h
Yield: 100 %

Procedure:
A solution of (5-dimethylaminomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (200 mg, 0.609 mmol) in a mixture of methanol (5 mL) and liquid ammonia (30 mL) is stirred for 6 days in an autoclave at 80° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as a red solid (182 mg, 0.609 mmol, 100%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=12.18 (bs, 1H), 7.75 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.42 (bs, 1H), 7.35 (d, J=8.6 Hz, 1H), 6.95 (bs, 1H), 3.67 (s, 2H), 3.16 (s, 2H), 2.62 (s, 6H). MS (ES+): 248 (M(C14H17NO3)+H)+. MS (ES+): 300
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Agent: N
Solvent: CO
Solvent: O
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Temperature: 45 °C
Yield: 52.8 %

Procedure:
A solution of 1.04 g (4.88 mmol) of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, mp 165° with decomposition at 169° C.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[OH:12][NH3+:13].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:13][OH:12])[NH2:5]
Reactant: N#Cc1cccc(F)c1F
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.0 g (35.2 mmol) of 2,3-difluorobenzonitrile were initially charged in 43 ml of ethanol, and a solution of 3.7 g (52.8 mmol) of hydroxylammonium chloride and 5.9 ml (4.3 g, 42.3 mmol) of triethylamine was added at RT. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 5.7 g (94% of theory)
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[CH:32]=O>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:32][C:31]1[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:29]([O:28][CH3:27])[CH:30]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(=O)c4ccccc4oc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)-4-acetylxanthen-9-one (2.4 g, 0.0075 mol) and 3, 4, 5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.2 g of product m.p. 153-55° C., 1H NMR (CDCl3) δ:1.69 (s, 3H); 1.72 (s, 3H); 3.85-3.91 (m, 9H); 4.73 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 6.78 (s, 2H); 7.03 (d, 1H, J=16 Hz); 7.09 (d, 1H, J=8.8 Hz); 7.23-7.42 (m, 2H); 7.27 (d, 1H J=16 Hz); 7.80-7.87; (m, 1H); 8.32 (d, 1H, J=8.8 Hz); 8.44 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C[C@@H](O)C[C@H](N(C)C)[C@@H](O)C=O.[F:64]OC(F)(F)F.Cl(F)(=O)(=O)=O>>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:64])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: FOC(F)(F)F
Agent: C[C@@H](O)C[C@@H]([C@@H](O)C=O)N(C)C
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 35 %

Procedure:
According to such a synthesis an enol-ether function (2) is generated in the molecule of erythromycin A (1) and subsequently the N-dimethyl group of desosamine is protected as N-oxide (3) to avoid the partial or total N-demethylation of the basic sugar during the fluorination; fluorination of (3) with trifluoromethyl hypofluorite or perchloryl fluoride, followed by hydrogenolysis, gives (8S)-8-fluoroerythromycin A (5). As a matter of fact, by operating according to the disclosure of the second Application erythromycin A can be converted into (8S)-8-fluoroerythromycin A, with a yield of about 35% in four subsequent steps (scheme II):
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C#N)c(NS(=O)(=O)c2ccc(F)cc2)c1
Temperature: 0 °C
Yield: 43.7 %

Procedure:
The title compound was synthesized by reacting 2-amino-4-methylbenzonitrile (0.25 g, 1.89 mmol) and 4-fluoro-benzenesulphonyl chloride (0.37 g, 1.89 mmol) in 2 mL of dry pyridine, following the reaction procedure of 6.29 The concentrated reaction mixture was poured into ice cold water (300 mL), and resulting pale white solid was filtered, washed with water and dried to gave 13 (0.24 g, 42.8%). Crystallization with EtOH gave (0.15 g) white amorphous solid, mp: 130-132° C.; IR (CHCl3) 3260, 2226, 1376, 1340, 1171, 1156 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.42 (s, 3H, CH3) and 6.90-7.83 (m, 7H, aromatic). HRMS calcd 313.0417 (C14H11FN2O2S.Na+), found 313.0418.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:7]=[C:2]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Product: FC(F)c1nc2ccccc2n1-c1nc(-c2cccnc2)cc(N2CCOCC2)n1
Yield: 77 %

Procedure:
Using a similar procedure to Example 47, reaction of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole (International Publ. No. WO 2008/032028, the disclosure of which is incorporated herein by reference in its entirety) and 3-pyridinylboronic acid gave 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(3-pyridinyl)-2-pyrimidinyl]-1H-benzimidazole in 77% yield: mp (CH2Cl2/hexanes) 172-179° C.; 1H NMR (DMSO-d6) δ 9.44 (d, J=2.2 Hz, 1H), 8.75 (dd, J=4.8, 1.5 Hz, 1H), 8.61 and 8.59 (2m, 1H), 8.39 (d, J=8.20 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.82 (t, JHF=52.8 Hz, 1H), 7.62 (dd, J=8.0, 4.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.46-7.42 (m, 1H), 3.88-3.84 (m, 4H), 3.79-3.77 (m, 4H); Anal. Calcd. for C21H18F2N6O1.9H2O: C, 49.1; H, 4.8; N, 15.6. Found: C, 49.0; H, 4.4; N, 15.0%
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[Cl:12].CCN(C(C)C)C(C)C.[O:22]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:27]([CH:24]1[CH2:25][CH2:26][O:22][CH2:23]1)=[O:28]
Reactant: O=C(Cl)C1CCOC1
Reactant: Nc1c(Cl)cc(O)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.40 g (2.12 mmol) 4-amino-3-chloro-5-nitrophenol were placed in 5 mL DCM. 0.44 mL DIPEA and 0.34 g tetrahydrofuran-3-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.34 g tetrahydrofuran-3-carbonyl chloride was added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[F:23][C:24]([F:37])([F:36])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:24]([F:37])([F:36])[F:23])=[CH:32][N:31]=3)=[O:34])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=525.2.