Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[C:6](OC)=[N:7][CH:8]=1.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]([CH2:2][Cl:1])=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncc(CCl)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CCl)cnc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a cold solution of 5-(chloromethyl)-2-methoxy-3-(trifluoromethyl)pyridine (0.3 g, 1.33 mmol) in DMF (0.6 mL) was added dropwise POCl3 (1.02 g, 6.65 mmol). The reaction was stirred for 1 h at 100° C. in a sealed tube. The reaction was cooled to room temperature, and poured onto ice water (10 mL). The reaction was extracted with DCM (thrice) and the combined organic layer was washed with water and brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to provide the title compound (0.20 g). LCMS m/z=230.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 4.62 (s, 2H), 8.06 (d, J=2.3 Hz, 1H), 8.57 (d, J=2.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][C:12]([O:14]C)=O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[NH3:16].Cl>CO.O>[NH2:16][C:12](=[O:14])[CH2:11][NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: COC(=O)CNC(=O)c1nccnc1O
Reactant: N
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)CNC(=O)c1nccnc1O
Reaction time: 1 h

Procedure:
In 4 mL of methanol is suspended 0.19 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)carbonyl]-amino}acetate. The suspension is saturated with ammonia by introducing gaseous ammonia thereinto under ice-cooling for 30 minutes. The resulting mixture is stirred at the same temperature as above for 1 hour and then at ambient temperature for 15 hours. The solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in a mixture of 4 mL of water and 1 mL of methanol. To the resulting solution is added 0.9 mL of 1 mol/L hydrochloric acid. The deposited crystals are collected by filtration to obtain 0.16 g of N2-(2-amino-2-oxoethyl)-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:29]([NH:28][C:10]3[CH:11]=[C:12]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)[CH:19]=[CH:18][N:17]=4)[CH:13]=[CH:14][C:9]=3[F:8])=[O:38])=[CH:35][CH:34]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cc(Nc2nccc(-c3cccnc3)n2)ccc1F)c1ccc(CCl)cc1
Product: CN1CCN(Cc2ccc(C(=O)Nc3cc(Nc4nccc(-c5cccnc5)n4)ccc3F)cc2)CC1
Yield: 95.7 %

Procedure:
1-Methylpiperazine (0.58 g, 5.77 mmol) and N-[4-fluoro-3-(4-chloromethylbenzoyl amino)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.31 mmol) were reacted according to the same procedure as Example 1 to give 4-(4-methylpiperazin-1-ylmethyl)-N-[2-fluoro-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH3:23])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 4-(4-bromophenyl)-phenol (4.06 g, 16.3 mmol) in acetone (30 mL) at room temperature, was added 4.5 eq K2CO3 (4.0M, 18 mL, 73.3 mmol) in water and 4.0 eq Iodoethane (5.26 mL, 65.2 mmol). The reaction mixture was stirred overnight, and heated to reflux for 6 hrs. The product was crystallized out of the solution, and filtered. The crude product was recrystallized from hexane to provide ethyl 4-(4-bromophenyl) phenyl ether (4.1 g, 91%) as an white crystal.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[CH3:13][N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:15].[B-](F)(F)(F)F.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:13][N:14]([CH3:15])[C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (500 mg, 2.92 mmol) in DMF (5 ml) under inert gas atmosphere was treated with TBTU (1030 mg, 3.2 mmol), dimethylamine hydrochloride (262 mg, 3.2 mmol) and N,N-diisopropylethylamine (2.0 ml, 11.7 mmol) and stirring was continued for 4 h. All volatiles were removed and the crude product was extracted with water and ethyl acetate. The organic phase was washed with sodium bicarbonate and the aqueous phases were back-extracted with ethyl acetate and dichloromethane. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a dichloromethane/methanol gradient as white solid (230 mg, 40%).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][OH:26]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH2:25][OH:26])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: OC[C@H]1CCCN1
Solvent: CS(C)=O
Product: OC[C@H]1CCCN1c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 400 ml (4 equivalents) of (R)-(−)-2-pyrrolidinemethanol, and the mixture is then heated at 120° C. for approximately 5 hours. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to dryness and the dry product is taken up in CH2Cl2, then partial drying is carried out. 258 mg of expected product are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:40])[CH2:26][N:25]([C:27]2[CH:28]=[C:29]([NH2:39])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:24][CH2:23][O:22]1.Cl.O1CCOCC1.CN1C(=O)CCC1>>[CH3:20][C:21]1([CH3:40])[O:22][CH2:23][CH2:24][N:25]([C:27]2[CH:28]=[C:29]([NH:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOC(C)(C)C2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (66.3 mg, 0.24 mmol; described herein), 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine (71.0 mL, 0.243 mmol, described herein), 4.0M hydrochloric acid in 1,4-dioxane (60 μL, 0.24 mmol), and NMP (350 μL, 3.6 mmol), and heating in a microwave at 160° C. for 3 h. Purification afforded N-(5-(2,2-dimethyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.5, 1.2 Hz), 7.86-7.95 (2H, m), 7.78-7.86 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.40 (1H, ddd, J=6.9, 5.0, 1.8 Hz), 7.28-7.33 (1H, m), 6.83 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.72-3.84 (3H, m), 3.65 (1H, t, J=5.9 Hz), 3.09-3.33 (4H, m), 2.80-2.93 (2H, m), 2.74 (2H, s), 2.37 (3H, s), 1.25-1.31 (4H, m). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([C:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(O)[C:22]#[CH:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([C:21]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]=2[CH:23]=[CH:22]1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: Oc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(ccc4ccccc34)O2)cc1
Reaction time: 1.5 h
Yield: 66 %

Procedure:
A mixture of 2-naphthol (3.23 g;0.0224 mol), 1,1-dianisylprop-2-yn-1-ol (6.00 g;0.0224 mol), acidic alumina Brockmann 1(6 g) and toluene (250 ml) was heated and stirred for 1.5 h, cooled, filtered and the solid washed with toluene. The filtrate was evaporated to give a pale purple tacky solid which was washed with pet. ether (40-60)/diethyl ether to yield crude product (7.07 g). Purification of the solid by crystallisation from ethylacetate gave 3,3-dianisyl-3H-naphtho[2,1-b]pyran as a white solid (5.52 g;66% yield), m.pt 176°-177° C. ##STR10##
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:29]=[CH:28][C:11]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[C:20]([NH2:22])[C:19]([C:23]#[N:24])=[C:18]([O:25][CH2:26][CH3:27])[N:17]=3)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:32])C.OO.O>CN(C)C=O>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[C:20]([NH2:22])[C:19]([C:23]#[N:24])=[C:18]([O:25][CH2:26][CH3:27])[N:17]=3)=[O:15])=[CH:28][CH:29]=2)=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CCOc1nc(C(=O)NCc2ccc(Sc3ccccc3)cc2)cc(N)c1C#N
Agent: OO
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCc2ccc(S(=O)c3ccccc3)cc2)cc(N)c1C#N
Yield: 70 %

Procedure:
A mixture of Example 161B (61 mg, 0.15 mmol), 2 mL of acetic acid, 0.15 mL of hydrogen peroxide (30% solution in water) in 0.5 mL of N,N-dimethylformamide was stirred at room temperature for 2 h. Water was added, the resulting precipitate was then filtered. The solid was triturated with methanol to provide the titled compound as a beige solid (44 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H), 4.43-4.53 (m, 4H), 7.05 (s, 1H), 7.29 (bs, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.46-7.55 (m, 3H), 7.63-7.72 (m, 4H), 9.08 (t, J=6.4 Hz, 1H). MS (ESI+) m/e=421 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[C@@H:10](CC([O-])=O)[CH2:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].C([O-])([O-])=[O:30].[K+].[K+].CC(O)=O>CO>[NH2:23][C:19]1[NH:20][C:21](=[O:22])[C:16]2[S:15][C:14](=[O:24])[N:13]([C@@H:11]3[O:12][C@H:8]([C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH3:7])[CH2:9][C@H:10]3[OH:30])[C:17]=2[N:18]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of [(2R,3R,5S)-5-[(1S)-1-acetoxypropyl]-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 6h, 210 mg, 0.5 mmol) in methanol (25 mL) was added K2CO3 (136 mg, 1 mmol). After being stirred at room temperature for 10 min, the reaction was adjusted to pH 7.0 by addition of HOAc (120 mg, 2 mmol), concentrated in vacuo and the residue was purified by preparative HPLC to afford 66.7 mg of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate (Example 6) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:8]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
contacting said 2,5-bis(2,2,2trifluoroethoxy)benzoic acid chloride with 2-aminomethylpyridine to provide 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.[C-:14]#[N:15].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:14]#[N:15])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 15 in dimethylformamide (0.3 M) at room temperature under nitrogen was added potassium cyanide (1.2 eq). The reaction was stirred at room temperature overnight. The reaction was diluted with H2O then extracted with ethyl acetate (3×). The organic phases were combined, washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (26%) 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 4H), 3.74 (s, 2H), 3.70 (s, 3H) 3.64 (s, 2H).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:21])[O:12][CH2:13][C:14]2[O:15][C:16](=[O:20])[O:17][C:18]=2[CH3:19])=CC=1)([O-])=O.[NH2:22][C:23]1[S:27][N:26]=[C:25](/[C:28](=[N:56]/[OH:57])/[C:29]([NH:31][C@@H:32]2[C:39](=[O:40])[N:38]3[C@@H:33]2[S:34][CH2:35][C:36](/[CH:44]=[C:45]2/[C:46](=[O:55])[N:47]([C@@H:50]4[CH2:54][CH2:53][NH:52][CH2:51]4)[CH2:48][CH2:49]/2)=[C:37]3[C:41]([OH:43])=[O:42])=[O:30])[N:24]=1.CC(C)=O>CS(C)=O>[NH2:22][C:23]1[S:27][N:26]=[C:25](/[C:28](=[N:56]/[OH:57])/[C:29]([NH:31][C@@H:32]2[C:39](=[O:40])[N:38]3[C@@H:33]2[S:34][CH2:35][C:36](/[CH:44]=[C:45]2/[C:46](=[O:55])[N:47]([C@@H:50]4[CH2:54][CH2:53][N:52]([C:11]([O:12][CH2:13][C:14]5[O:15][C:16](=[O:20])[O:17][C:18]=5[CH3:19])=[O:21])[CH2:51]4)[CH2:48][CH2:49]/2)=[C:37]3[C:41]([OH:43])=[O:42])=[O:30])[N:24]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Reactant: Cc1oc(=O)oc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of 13.2 g (44.72 mmol) of carbonic acid 5-methyl-2-oxo-[1,3]dioxol4-ylmethyl ester 4-nitro-phenyl ester in 200 ml of dimethylsulfoxide are added 20.0 g of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The mixture is stirred under argon at room temperature for 4 hours and 1000 ml of acetone are added. The slightly turbid solution is clarified by filtration over a fluted filter. To the clear motherliquour are added 34.0 ml (34 mmol) of a 1N solution of sodium-2-ethylcaproate in acetone at room temperature during 20 minutes. The slightly yellow suspension is stirred for 10 minutes at room temperature, the solid is collected by filtration, washed with 1000 ml of acetone and 1000 ml of n-pentane and dried under high vacuum. The product is suspended in 600 ml of acetone and stirred at room temperature for 2 hours. The product is collected by filtration and dried under high vacuum to yield 23.94 g of the title compound as an off-white powder.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[CH2:18]([O:20][C:21](=[O:35])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[C:25](=[O:33])[C:24]1=[O:34])[CH3:19].O1C2C=CC(O)=CC=2OC1.[O:46]1[C:50]2[CH:51]=[C:52]([OH:55])[CH:53]=[CH:54][C:49]=2[CH2:48][CH2:47]1>>[CH2:18]([O:20][C:21](=[O:35])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[C:25]([OH:33])([C:53]2[C:52]([OH:55])=[CH:51][C:50]3[O:46][CH2:47][CH2:48][C:49]=3[CH:54]=2)[C:24]1=[O:34])[CH3:19]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl(5-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (br, 1H), 7.31-7.24 (m, 2H), 6.92 (d, 1H), 6.68 (s, 1H), 6.46 (s, 1H), 4.53-4.46 (m, 2H), 5.09-4.40 (d, 2H), 4.18 (q, 2H), 3.08-2.88 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 387.8 (M−17).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][OH:13])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].I(O)(=O)(=O)=[O:15]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:15])=[O:13])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)c1sc(CO)cc1C#N
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C(=O)O)cc1C#N
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 3-Cyano-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (0.1342 g, 0.68 mmol) and Periodic Acid (0.34 g, 1.50 mmol) in MeCN (9.5 ml) was stirred for 30 min. A solution of PCC (0.010 g, 0.015 mmol) in MeCN (0.5 ml) was added. After 1 h, the reaction mixture was diluted with EtOAc (50 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 0.13 g (90%) of beige solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]2=[O:26])=[CH:15][CH:14]=1.N12CCN(CC1)CC2>O1CCCC1>[O:26]=[C:20]1[CH2:21][CH2:22][CH2:23][C:24](=[O:25])[N:19]1[C:16]1[CH:17]=[N:18][C:13]([O:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCCC(=O)N1c1ccc(O)nc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(N2C(=O)CCCC2=O)cn1)c1ccccc1
Yield: 76.6 %

Procedure:
A solution of N-methyl-N-phenyl carbamoyl chloride (170 mg, 1.00 mmol), 6′-hydroxy-4,5-dihydro-3H-[1,3]bipyridinyl-2,6-dione (206 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, first ethyl acetate:heptane 75:25 followed by pure ethyl acetate). Evaporation of the solvent yielded the title compound (260 mg, 77% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:16])[C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc(OCc2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(OCc2ccccc2)cc1Br
Reaction time: 2 h

Procedure:
To a solution of 5-(benzyloxy)pyridin-2-amine (10.2 g) in acetic acid (50 mL) was added bromine (2.61 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.50 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([OH:11])=[C:9]([OH:12])[N:8]=[C:7]([CH2:13][C:14]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:6]=1)=O.[CH3:25][NH2:26]>C1COCC1>[CH3:25][NH:26][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: CN
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Temperature: 110 °C
Yield: 36 %

Procedure:
To a solution of 5,6-dihydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid methyl ester (55 mg, 0.167 mmol) in THF (2 ml) was added 2M solution of methyl amine in THF (0.419 mL, 0.838 mmol) under nitrogen atmosphere in a microwave vessel. The reaction mixture was heated in a microwave oven at 110° C. for 10 min, then cooled and evaporated to dryness. The residue was washed with water and 30% ethyl acetate in hexane to get the title compound as an off-white solid (0.020 g, 36%). LCMS: m/z=327.8 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[OH-].[Na+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.C(Cl)Cl.O.O>[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:2]2[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1CN(S(=O)(=O)c2ccc(I)cc2)C1
Yield: 43.8 %

Procedure:
To a stirred solution of azetidine-3-carboxylic acid hydrochloride (1.0 g, 7.27 mmol) in DCM (25 mL) is added 5N aqueous NaOH (10 mL) and water (10 mL). p-Iodobenzenesulfonyl chloride (2.41 g, 7.98 mmol) is added portionwise. After 18 h the reaction mixture is diluted with DCM/water. The basic aqueous layer is acidified with 5N aqueous HCl. The resultant precipitate is filtered, washed with water and MeCN. Drying in air gives 1.17 g (44%) of 1-[(4-iodophenyl)sulfonyl]azetidine-3-carboxylic acid. m/z=368 [M++H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (9.41 g, 0.048 mol) in dichloromethane (200 mL) at room temperature was added iPr2NEt (14.1 g, 0.110 mol), followed by MsCl (5.5 g, 0.048 mol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (1:1 hexane:ethyl acetate). The desired compound was obtained as an oil (11.06 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:21]1[S:22][C:23]([CH:27]=[O:28])=[C:24]([Cl:26])[N:25]=1>O1CCCC1>[Cl:26][C:24]1[N:25]=[C:21]([N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:8])[S:22][C:23]=1[CH:27]=[O:28]
Reactant: CNCc1ccc(Cl)cc1
Reactant: O=Cc1sc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119525.2 %

Procedure:
To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) and N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 3 g, 0.01 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was collected by filtration and washed with hexanes to provide the desired compound as a light-yellow solid (551, 3.6 g, 90%).