Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:16](O)[CH2:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])C=Cc1cc(F)cc(F)c1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Add acetic anhydride (160 mL) to a solution of 1-(3,5-difluorophenyl)-2-nitroethanol (330 g) and 4-dimethylaminopyridine (18 g) in dichloromethane (1000 mL), over 30 minutes and stir the reaction mixture overnight. Dilute with dichloromethane (600 mL) and wash with 2% aqueous hydrochloric acid, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, dry (magnesium sulfate) and concentrate. Wash the crude with hexanes to give the desired compound (220 g).
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:2]3[C:3](=[CH:21][C:22]([F:26])=[C:23]([F:25])[CH:24]=3)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O

Procedure:
19.2 g of ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-(4-fluoroanilino)-acrylate was dissolved in 95 ml of dimethylformamide, and 8.3 g of potassium carbonate was added thereto. The mixture was heated for 60 minutes at a temperature of from 100° to 110° C. The reaction mixture was returned to room temperature and poured into water. Precipitated crystals were collected by filtration and washed with ethonol. 15.6 g (90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([CH3:13])[CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([CH3:13])[CH2:9][C:10]([NH2:12])=[S:37])=[CH:4][CH:3]=1
Reactant: C[SH](CC(N)=O)(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[SH](CC(N)=S)(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-[bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetamide (0.5 g) in toluene (20 ml) was treated with Lawesson's reagent (0.26 g) at room temperature under Argon and stirred for 1.5 hours at 80° C. After pouring into saturated brine the organics were extracted with dichloromethane (3×). Drying of the combined organic extracts (Na2SO4), filtration, concentration and flash-chromatography of the residue gave the title compound (42%; Isolated as an oil).
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[C:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1)=[O:4].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.N1C=CC=CC=1>>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][S:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([Cl:19])([Cl:18])[Cl:1])[CH2:13]2)(=[O:16])=[O:15]
Reactant: Nc1nccs1
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(Cl)(Cl)Cl
Temperature: 60 °C
Yield: 71.4 %

Procedure:
2-(2,2,2-Trichloro-acetyl)-2,3-dihydro-1H-isoindole-5-sulfonyl chloride (0.25 g, 0.7 mmol), was added to a stirring solution of 2-aminothiazole (0.07 g, 0.7 mmol) and pyridine (57 μl, 0.7 mmol) and heated to 60° C. for 1 h. The reaction mixture was then partitioned between CH2Cl2 and aqueous 1N HCl solution. The organic layer was concentrated in vacuo and purified via silica gel chromatography (3% MeOH in CH2Cl2) to give the sulfonamide as a tan solid (200 mg, 0.5 mmol, 67% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=426.0; tR=2.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: Cc1cc(C)cc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3,5-dimethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:19])[C:3]=1[C:20](=O)[CH2:21][CH3:22].[CH2:24]([O:26][NH2:27])[CH3:25].Cl>O1CCCC1>[CH2:24]([O:26][N:27]=[C:20]([C:3]1[C:4](=[O:19])[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1])[CH2:21][CH3:22])[CH3:25]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 1.5 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was kept at room temperature for 15 hours and poured into ice water. And then the mixture was acidified with hydrochloric acid and it was extracted with chloroform. The chloroform solution was washed with water and extracted with 15 ml of an aqueous solution cotaining 5% of sodium hydroxide. The solution was acidified with hydrochloric acid and the crystal sedimented was extracted with chloroform and the solution was washed with water and it was dried with magnesium sulfate. Then, it was distilled off under a reduced pressure and thus, 1.4 g of the objective compound was obtained. It was colorless crystals having a melting point of 115°-116° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]2[C:5]1=[N:6][C@@H:7]1[CH2:16][CH2:15][CH2:14][C@@H:8]12.C1(C)C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>C1COCC1>[CH3:3][N:4]1[C:12](=[O:13])[C:11]2=[CH:26][NH:27][CH:28]=[C:10]2[N:9]2[C@H:8]3[CH2:14][CH2:15][CH2:16][C@H:7]3[N:6]=[C:5]12
Reactant: CN1C(=O)C=CN2C1=N[C@@H]1CCC[C@@H]12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c[nH]cc2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Sodium hydride (95%, 112 mg, 4.44 mmol) is suspended in 3 mL of anhydrous THF, and then a mixture of (3aS,8aR)-7-Methyl-1,2,3,3a,7,8a-hexahydro-3b,7,8-triaza-cyclopenta[a]inden-6-one (283 mg, 1.48 mmol) and p-toluenesulfonylmethyl isocyanide (97%, 347 mg, 1.77 mmol) in 5 mL of anhydrous THF is added dropwise. The mixture is stirred at room temperature for an hour, and then quenched with water. The mixture is extracted with CH2Cl2 (5×10 mL). The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is evaporated to dryness under reduced pressure to give crude product (320 mg, yield 94%) as brown solids, which is used for the next reaction without further purification. MS (ESI) m/z 231.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.Cl[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C>CCO>[CH3:17][N:16]1[C:12]([N:7]2[CH2:6][CH2:5][NH:4][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:8]2)=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[N:15]1
Reactant: FC(F)(F)C1CNCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(C(F)(F)F)C1
Temperature: 140 °C
Yield: 104 %

Procedure:
A mixture of (±)-2-(trifluoromethyl)piperazine (1 g, 6.2 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.1 g, 13 mmol), DIPEA (2.4 g, 18.6 mmol) in EtOH (10 mL) was heated in a microwave oven at 140° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (10:1) as eluting solvents to afford (±)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-(trifluoromethyl)piperazine as a yellow oil (1.8 g, 99%). MS (ESI) m/z: 280 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:12])[CH3:11].N1C=CC=CC=1>[Cl-].[Na+].O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: CC(C)N1CCNCC1
Reactant: Cc1cc(Br)ncc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(N2CCN(C(C)C)CC2)ncc1Br
Yield: 90.5 %

Procedure:
To a solution of 2,5-dibromo-4-methyl-pyridine (5.0 g, 20 mmol) and isopropyl-piperazine (25.6 g, 200 mmol) were added pyridine (2.06 g, 206 mmol). The reaction mixture was refluxed for 5 h under a nitrogen atmosphere. Brine was added and the mixture was extracted with EtOAc. The organic extract was washed with brine and 0.5 N hydrochloric acid. The acidic layer was made alkaline with Na2CO3 to pH 8 and then extracted with CH2Cl2. The organic extract was dried (Na2SO4) and concentrated to give 5.4 g (90%) of 1-(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH:46]([CH3:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[OH:57][CH2:56][CH2:58][NH:59][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH:22]([CH3:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:15]([CH3:30])([CH3:31])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:38][C:39]([CH3:54])([CH3:55])[N:40]([O:45][CH:46]([CH3:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]([CH3:43])([CH3:44])[CH2:42]2)[N:3]=1
Reactant: CC(ON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC(C)c4ccccc4)C(C)(C)C3)n2)CC1(C)C)c1ccccc1
Reactant: NCCO
Product: CC(ON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OC(C)c4ccccc4)C(C)(C)C3)n2)CC1(C)C)c1ccccc1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis{N-[1-(α-methylbenzyloxy)-2,2,6,6-tetramethylpiperidin-4-yl]butylamino}-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]1)[C:5]2=[N:18]S(C(C)(C)C)=O.Cl.CCOCC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH2:7][C:6]3([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]3)[C:5]2=[NH:18])=[CH:9][CH:10]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 19 Step 1, mixture of isomers, 2 g, 4.85 mmol) in anhydrous 1,4-dioxane (25 mL) was added 4M HCl in 1,4-dioxane (12.12 mL, 48.50 mmol). A white precipitate was formed immediately and the resulting cloudy mixture was stirred under a nitrogen atmosphere at r.t. for 90 min. Et2O (30 mL) was added and the solid was filtered off and washed with Et2O. The solid was partitioned between DCM (40 mL) and sat. aq. NaHCO3 (40 mL). The phases were separated and the organic layer concentrated. The crude title compound (1.41 g) was used directly in the next step. MS (EI) m/z 307 M+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.F[C:12]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=1[NH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:14][C:13]2[CH:12]=[CH:18][C:17]([O:19][CH3:20])=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: ClCc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,4-dichloro-5-chloromethyl-pyrimidine (3.70 g, 18.7 mmol) (from Example 1b supra), 2-fluoro-4-methoxy-phenylamine (2.40 g, 17.0 mmol) (from Example 14a supra) and potassium carbonate (4.70 g, 34.0 mmol) in acetone (100 mL) was stirred at room temperature for 18 hours. The precipitate was filtered off and the solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This residue was purified by flash chromatography eluting with ethyl acetate-hexanes (1:4) to give [(2,4-dichloropyrimidin-5-yl)methyl]-(4-methoxyphenyl)-amine. (Yield 3.99 g, 78%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.02 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]2[O:9][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:5]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(O)c(C)c1
Product: Cc1cc(C)c2occ(-c3ccccc3)c2c1

Procedure:
Using the method of Example 17 and starting with 2,4-dimethylphenol and α-bromoacetophenone and cyclizing at 50°-60° C., 5,7-dimethyl-3-phenylbenzofuran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNS(C)(=O)=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.5 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (162 mg) in ethanol (0.5 mL) was added 4.0 M hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol-water to give the title compound (109 mg) as colorless crystals.
Reaction SMILES: N#N.[C@@H:3]1([N:12]2[C:21](=[O:22])[C:20]3[NH:19][CH:18]=[N:17][C:16]=3[N:15]=[C:13]2[NH2:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@@H:4]1[OH:5].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[C@@H:3]1([N:12]2[C:21](=[O:22])[C:20]3[NH:19][CH:18]=[N:17][C:16]=3[N:15]=[C:13]2[NH:14][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@@H:4]1[OH:5]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1nc2nc[nH]c2c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: N#N
Product: CC(C)C(=O)Nc1nc2nc[nH]c2c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
introducing an acyl group at the N2 position of 1-β-D-arabinofuranosyl guanine with an acylating agent, for example, using isobutyryl chloride under conditions suitable for obtaining 1-β-D-arabinofuranosyl-N2-isobutyryl guanine,
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:16][N+:17]([CH3:26])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>>[CH3:26][N:17]([CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5]1[N:1]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:2]=[CH:3][CH:4]=1)[CH3:16]
Reactant: Cc1ccccc1C=[N+](C)C
Reactant: NC(=S)c1ccccc1-n1cccc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cccn1-c1ccccc1C(N)=S)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-thiobenzamide and dimethyl-(2-methyl-benzylidene)-ammonium chloride.
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])[CH2:8][NH:7][C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C=O.[CH:54](O)=O.O>CC(C)=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]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:54])[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)CN[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=CO
Agent: C=O
Solvent: O
Solvent: CC(C)=O
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@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 58 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 0.25 L three-necked round bottom flask equipped with a mechanical stirrer, a condenser and thermometer, 25 g of desmethyl-azithromycin was dissolved in 102 mL of acetone. Formaldehyde (5.3 mL) and formic acid (2.6 mL) were added and the clear solution was heated to reflux (˜58° C.). The mixture was maintained under reflux for 3 hours then cooled to less than 40° C. and 102 mL of water was added. The acetone was separated from the reaction mixture by distillation under low vacuum (˜300 mbar). The distillation was stopped when the temperature of the liquid phase reaches ˜40° C./300 mbar. Activated carbon SXI (1.25 g) was added and the suspension was mixed for 1 hour. Then the activated carbon was separated from the solution by filtration on a Büchner filter containing Hyflow. The filter cake was washed with 102 mL of water. The pH was adjusted with an NaOH solution of 47% to 10-10.5 (˜3.14 g). A massive precipitation of Azithromycin was observed. After stirring the suspension for 1 hour, the crude azithromycin was separated by filtration, washed twice with 25 mL of water and dried at 40° C. in a vacuum oven for>24 hours. After drying, 19.7 g of crude azithromycin was obtained (yield 77% based on weight). No impurities that were derivatives of azithromycin were detected.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12](=[O:38])[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:16][CH2:15]1)C.[OH-].[Li+]>O1CCCC1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:17]2([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:18][CH2:19][CH:14]([CH2:13][C:12]([C:8]3[O:9][CH:10]=[CH:11][C:7]=3[CH2:6][CH2:5][C:4]([OH:39])=[O:3])=[O:38])[CH2:15][CH2:16]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CCc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product from Example 146 (100 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was treated with a solution of lithium hydroxide (80 mg, 3.3 mmol) in water (2 mL). The reaction was stirred at room temperature for 3 hours, then evaporated and the residue taken up in water and ethyl acetate. The ethyl acetate layer was evaporated and purified by preparative thin layer chromatography (1% acetic acid, 33% ethyl acetate, 33% hexane, 33% dichloromethane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCSCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J7) (189 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (170 mg, 0.56 mmol) according to the general procedure M. Obtained as a yellow solid (302 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)CN(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccccc2N)cc1
Yield: 90.1 %

Procedure:
To a solution of 5.14 g (14.1 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate in 50 ml of methanol-tetrahydrofuran (1:1) was added 2.86 ml of 10 N NaOH and the mixture refluxed for 2 hours. The solvent was removed under vacuum and the residue partitioned between water and ether. The water layer was separated and acidified with 2 N citric acid. The solid was filtered, washed with H2O and dried in a vacuum oven at room temperature to give 4.45 g (91%) of crystals, m.p. 145°-147° C. Anal. for C16H18N2O5S: Calc'd: C,54.9; H,5.2; N,8.0; Found: C,55.1; H,5.2; N,7.9.