Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3](/[C:9](/Cl)=[N:10]\[OH:11])[CH:2]=1.CO[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C.O>ClCCl>[Cl:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][O:11][N:10]=2)=[CH:2][CH:1]=1
Reactant: COC=CC(=O)OC
Reactant: O/N=C(/Cl)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1conc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
N-Hydroxy-4-chloromethylbenzenecarboxyimidoyl chloride (15.27 g, 74.82 mmol) was dissolved in dichloromethane (300 ml), methyl 3-methoxyacrylate (10.43 g, 89.82 mmol) was added, and triethylamine (21 ml, 151 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (9.67 g, 51%).
Reaction SMILES: C(#N)[CH:2]([CH2:4][C:5]#[N:6])O.C(O)(=O)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19]>C(O)C.C(OCC)(=O)C>[S:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:2]1[CH2:4][C:5]#[N:6]
Reactant: Nc1ccccc1S
Reactant: N#CCC(O)C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCc1nc2ccccc2s1
Reaction time: 16 h

Procedure:
To a solution of malonitrile (6.61 g) and acetic acid (60 ml) in ethanol (100 ml) was added o-amino thio-phenol (7 ml) and the reaction was conducted at room temperature for 16 hours. This reaction mixture was diluted with ethyl acetate (200 ml) and washed with 5% aqueous sodium chloride solution. The organic layer was further washed with 3N NaOH (200 ml) and saturated NaCl solution (200 ml) and dried and the solvent was distilled off under reduced pressure. The residue was crystallized from IPE to give 2-benzothiazoleacetonitrile (13.8 g). This crystalline product (10.45 g) was dissolved in DMF (100 ml), and after addition of 60% sodium hydride (1.44 g) under ice-cooling, the solution was heated to 60° C. and stirred for 30 minutes. After cooling to room temperature, ethyl 6-bromohexanoate (5.31 ml) was added and the reaction was conducted at 60° C. for 30 minutes. After cooling to 10° C. or less, the reaction mixture was diluted with pure water (300 ml) and extracted with ethyl acetate (200 ml) twice. The pooled organic layer was washed with saturated aqueous sodium chloride solution and dried. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to provide ethyl 7-(benzothiazol-2-yl)-7-cyanoheptanoate (3.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:19]=[C:20]([C:24]4[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:6]=[C:5](SC)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:50]([NH2:52])[CH3:51].C1COCC1>ClCCl.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:33])[C:3]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:19]=[C:20]([C:24]4[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:6]=[C:5]([NH:52][CH2:50][CH3:51])[N:4]=1
Reactant: CSc1nc(N(C)C)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Reactant: CCN
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCNc1nc(N(C)C)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
(S)-5-[3-(7-Dimethylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (26.8 mg, 0.0573 mmol) obtained in Step 1 was dissolved in dichloromethane (5.0 mL), and the mixture was stirred at room temperature for 20 minutes after adding 3-chloroperbenzoic acid (22.8 mg, 0.0860 mmol). A saturated aqueous sodium bicarbonate solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in THF (2.0 mL), and the mixture was stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was further stirred at 90° C. for 135 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (Compound 159) (18.9 mg, 71%).
Reaction SMILES: [Cr](O)(O)(=O)=O.S(=O)(=O)(O)O.[OH2:11].[OH:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:38])[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21]>CC(C)=O.C(OCC)(=O)C>[C:13]([CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:38])[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])([OH:11])=[O:12]
Reactant: O
Reactant: O=C(COCCCO)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(O)CCOCC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
625 mg (6.25 mmol) of chromic acid, 0.65 ml of concentrated sulfuric acid and 2.9 ml of water were added to 1.36 g (3.66 mmol) of 3,3-diphenylpropyl 4-(3-hydroxypropoxy)-3-oxobutanoate in 17 ml of acetone, and they were stirred at room temperature for 1.5 hours. After the addition of water and extraction with ethyl acetate, the organic layer was washed with water and then saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH:14]=[O:15])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:13])[CH:14]=[O:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Temperature: 110 °C
Yield: 88.9 %

Procedure:
1420 g of 1-(p-tert.butylphenyl)-2-formyl-1-propene, prepared as described in paragraph (e), are mixed together with 6 g of 5% palladium/carbon and 6.8 g of soda in 20 ml of water at 70°-75° C. in a stirring autoclave. The autoclave is charged with hydrogen (8 atmospheres) and heated to 110° C. About 230 liters of hydrogen are absorbed after 12 hours. The crude 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde is treated with ether, washed neutral with water and dried over sodium sulphate. After removing the ether, the product is fractionally distilled in vacuo. After separating a first running and a last running, there are obtained 1275 g of 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde in 95% purity (about 88% of theory). Boiling point: 150°-152° C./15 mmHg; nD20 =1.5050.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([NH:36][CH3:37])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([NH:36][CH3:37])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:31])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CNC1
Product: CNC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(methylamino)azetidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Azetidin-3-yl-methyl-amine following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[O-:11][C:12]#[N:13].[K+].[CH3:15][OH:16]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:13][C:12]([O:16][CH3:15])=[O:11])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CO
Reactant: CCCCC(Br)C(=O)OC
Reactant: N#C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(NC(=O)OC)C(=O)OC
Yield: 75.6 %

Procedure:
14.63 grams of 2-bromohexanoic acid methyl ester, 8.52 grams of potassium cyanate and 7.85 grams of methanol were heated in 70 ml of dimethylformamide (DMF) at 100° C. for 45 minutes under vigorous stirring. After the cooling off of the reaction mixture the salts were filtered off and the filtrate concentrated in a vacuum. The viscous residue was taken up with 50 ml of acetone and the undissolved material filtered off. Subsequently the acetone was distilled off and the residue fractionated in the high vacuum. There resulted 10.75 grams (75.5%) of 2-methoxycarbonylaminohexanoic acid methyl ester having a boiling point of 78° C./0.007 mbar.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>O.CCO>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(F)cccc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(F)cccc1I
Temperature: 0 °C
Yield: 59.2 %

Procedure:
To a mixture of 2-iodo-6-fluorobenzaldehyde (45 mmol) in H2O (22.5 ml), EtOH (22.5 ml), and ice (20 g) was added hydroxylamine hydrochloride (3.19 g, 49.5 mmol, 1.1 eq.). Then, 112.5 mmol of 50% NaOH (4.5 g in 4.5 ml H2O, 2.5 eq.) was added with stirring. Enough ice to keep the temperature at 25-30° C. was added. The reaction was stirred for 2 h, acidified with conc. HCl to pH 4 (ice was added to keep the temperature at 25-30° C.), and extracted with Et2O. The combined organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel using ethyl acetate in hexanes (5%-10%) to give 2-iodo-6-fluorobenzaldehyde oxime (7.06 g, 59% over 2 steps) as an oil that solidified over time.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1cccs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1cccs1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 66 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 2-thiophenecarbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 66%. Melting point: 222-224° C. (Ethyl acetate-hexane)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[Cu][C:15]#[N:16]>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1>[C:15]([C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13])#[N:16]
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)c2c(c1C)C(=O)CC2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)c2c(c1C)C(=O)CC2
Reaction time: 6 h

Procedure:
A mixture of 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J. Het. Chem. 24, 677 (1987)] and 7.3 g (82 mmol) of copper(I) cyanide in 18 ml of DMF is stirred for 6 hours at 170°. The reaction mixture is then cooled to 100° and 200 ml of toluene and a solution of 31.2 g of iron(HI) chloride hexahydrate in 47 ml of water and 8.2 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is crystallised from ethyl acetate and ether and corresponds to starting compound (a). Beige crystals having a melting point of 160°-163° are obtained; IR (CH2C12): 2220, 1710 cm-1.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]1[CH:13]=[CH:12][C:11]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:10]1=2>>[C:1]1([C:20]2([OH:21])[C:10]3[S:9][CH:13]=[CH:12][C:11]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C1c2ccccc2-c2ccsc21
Product: OC1(c2ccccc2)c2ccccc2-c2ccsc21

Procedure:
from phenylmagnesium chloride and indeno[2,1-b]thiophen-8-one (prepared as described in Rawson and Wyberg, Rec. Trav. Chim. 90, 1971:46-55)
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[N:4][N:3]=[N:2]1.C([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])(OC(C)(C)C)=O.C(Cl)C[Cl:31]>>[Cl:31][C:11]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[C:7]([CH:10]=1)[CH2:8][NH:9][C:23](=[O:24])[C@@H:22]1[CH2:26][CH2:27][CH2:28][NH:21]1.[N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH:9][C:23](=[O:25])[C@@H:22]2[CH2:26][CH2:27][CH2:28][NH:21]2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccccc1-n1cnnn1
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Product: O=C(NCc1ccccc1-n1cnnn1)[C@@H]1CCCN1

Procedure:
The title compound was prepared essentially according to the EDC coupling procedure described in Example 26 using 1-[2-(1H-tetraazol-1-yl)phenyl]methanamine (Example 1, 55 mg, 0.31 mmol) and Boc-L-proline (67 mg, 0.31 mmol) followed by purification of the intermediate (silica gel chromatography, 50%–70% EtOAc/hexanes) and deprotection using 4.0 M HCl in dioxane. The hydrochloride salt of the title compound was isolated as a colorless gum: LCMS (M+H): 273.1. 1H NMR (CD3OD, 400 MHz): δ 9.58 (s, 1 H), 7.66–7.65 (m, 2 H), 7.59–7.55 (m, 1 H), 7.51–7.49 (m, 1 H), 4.39–4.26 (m, 2 H), 4.16 (m, 1 H), 3.31–3.28 (m, 2 H), 2.36–2.33 (m, 1 H), 1.98–1.87 (m, 3 H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:19][N:20]=[N:21][N:22]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.35 g (0.01 mol) of 7β-amino-3-[1-(2methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 2 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].N1C=CC=CC=1.[S:23]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24]1>ClCCl>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][S:23][CH:24]=1
Reactant: O=C(Cl)Cc1ccsc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccsc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of the product of Example 11B (30.2 mg, 0.13 mmol), pyridine (0.14 mL, 0.17 mmol), and 2-(thiophen-3-yl)acetyl chloride (24.0 mg, 0.15 mmol) in dichloromethane (0.4 mL) was stirred for 3 hours, concentrated, and chromatographed (20% acetone/hexanes) to give the title compound (33.8 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.82-11.94 (m, 1H), 8.44 (dd, J=7.9, 1.5 Hz, 1H), 8.11-8.17 (m, 1H), 8.00-8.09 (m, 2H), 7.36-7.58 (m, 2H), 7.14 (dd, J=4.9, 1.3 Hz, 1H), 3.74 (s, 2H); MS (ESI−) M/Z 352 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1>[CH3:16][C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.6 g, assumed 31.4 mmol) in 1,4-dioxane (126 mL) was added hydrazine monohydrate (8.5 mL, 175 mmol). The mixture was heated at 85° C. and stirred for 24 h. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was partitioned between DCM (200 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (8.04 g, >100% crude yield) as a dark orange oil. LCMS: (M+H)+: 254.9.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[NH2:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:23][C:19]1[N:18]=[C:17]([Cl:24])[N:16]=[C:15]2[C:20]=1[N:21]=[CH:22][N:14]2[C@@H:12]1[CH2:13][C@H:9]([NH:8][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:10]([OH:26])[C@H:11]1[OH:25]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](N)[C@@H](O)[C@H]1O
Reactant: CCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,2R,3S,5R)-3-Amino-5-(6-amino-2-chloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (intermediate for preparing Example 1) (20 mg, 39 μmol) and diisopropylethylamine (25 mg, 190 μmol) are placed in a flask with dry THF (1 ml). Propionyl chloride (3.6 mg, 39 μmol) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained, which can be purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.10 (s, 1H), 4.75 (m, 1H), 4.60 (m, 1H), 4.20 (m, 1H), 4.00 (m, 1H), 3.75 (m, 1H), 3.25 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H), MS (ES+) m/e 341 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4](I)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I.O>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: OC1CCNCC1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 80 °C
Yield: 11 %

Procedure:
To a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (150 mg, 0.46 mmol) and 4-hydroxypiperidine (56 mg, 0.56 mmol) in isopropyl alcohol (1 mL) was added 1,2-ethanediol (0.052 mL, 0.92 mmol), potassium phosphate (200 mg, 0.93 mmol), and copper(I) iodide (5 mg, 0.02 mmol). The reaction was heated at 80° C. overnight and then cooled to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexanes, to give the desired product (15 mg, 11%). LCMS calculated for C15H21ClNO3 (M+H)+: m/z=298.1. found: 298.0.
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][CH:55]=[CH:54][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:11]1[CH:14]([CH2:15][CH2:16][OH:17])[CH:13]([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[O:22])[CH3:19])[C:12]1=[O:34])=[O:9])([O-:3])=[O:2].CC(C)=[O:60].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:57]=[CH:56][CH:55]=[CH:54][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[N:11]1[C@@H:14]([CH2:15][C:16]([OH:60])=[O:17])[C@H:13]([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[O:22])[CH3:19])[C:12]1=[O:34])=[O:9])([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])C1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)C1CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])[C@@H]1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-(o-Nitrobenzyloxycarbonyltriphenylphosphoranylmethyl)-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(2'-hydroxyethyl)-2-azetidinone (0.1582 g, 0.20 mmol) (cf. Example 43, Step I) is dissolved in 5 ml acetone cooled to 0°. Jones Reagent (0.12 ml, 4N solution) is added dropwise over 3 minutes and the resulting solution is stirred at 0° for 10 minutes. Isopropanol (0.05 ml) is added and the mixture stirred for another 2 minutes. The reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is washed with saturated NaCl aqueous solution, dried and evaporated to give 0.132 g of crude acid which is used without further purification in the next step.