Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22]C(C=C)=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[N+]1([O-])CC[O:30]CC1.[CH3:34][C:35]([CH3:37])=[O:36]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:34]([CH:35]([OH:36])[CH2:37][OH:30])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Product: OCC(O)c1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a suspension of 2-(3-chlorophenyl)-N-(4-vinylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (0.098 g, 0.28 mmol) in acetone (10 mL) and water (5 mL) was added 4-methylmorpholine N-oxide (0.183 g, 1.4 mmol) and potassium osmate dihydrate (0.002 g, 0.0056 mmol). The mixture was stirred at rt for 16 h. After this time, the reaction mixture was absorbed onto silica and purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.063 g, 58%) as a light brown solid. MW=381.86. 1H NMR (DMSO-d6, 500 MHz) δ 8.82 (s, 1H), 8.30-8.22 (m, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.33 (d, J=8.5 Hz, 2H), 5.16 (d, J=4.5 Hz, 1H), 4.68 (t, J=6.0 Hz, 1H), 4.55-4.51 (m, 1H), 3.46 (1, J=6.0 Hz, 2H), 2.95-2.85 (m, 4H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 382 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH:6]1[CH2:18][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)[CH3:5].C(N(CC)CC)C.[O:36](C(OC(C)(C)C)=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40]([O:39][C:37]([N:10]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=2[C:8]2[CH2:7][CH:6]([C:4]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])([C:3]([O:2][CH3:1])=[O:28])[CH3:5])[CH2:18][C:9]1=2)=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
130 mg (0.31 mmol) (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester were dissolved in 7 mL CH2Cl2 at RT. 90 μL (0.62 mmol, 2 eq) triethylamine, 4 mg (0.031 mmol, 0.1 eq) DMAP and 81 mg (0.37 mmol, 1.2 eq) BOC2O were added. The reaction mixture was stirred for 2 hours. The reaction was quenched with 10 mL of an aqueous 1M solution of HCl. The organic layer was separated and the aquous layer was washed with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield to 152 mg (94%) (RS,SR)-2-(1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester as a white powder, M: 535 (MNH4+).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:27][C:26]2[CH:25]=[N:24][C:23]([CH3:28])=[CH:22][C:21]=2[CH2:20]1)=[O:18])[CH3:15].[CH3:30]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:9]2[C:10]3[CH2:30][CH2:2][CH2:3][CH2:4][C:5]=3[CH:6]=[CH:7][CH:8]=2)=[O:13])[CH2:27][C:26]2[CH:25]=[N:24][C:23]([CH3:28])=[CH:22][C:21]=2[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2cnc(C)cc2C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc2c1NCCC2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cnc(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (240 mg, 1.36 mmol), 6-amino-3-methyl-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester (not pure, 300 mg, 1.36 mmol), HATU (608 mg, 1.60 mmol) in anhydrous DMF (10 mL) is added DIPEA (264 μL, 1.60 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a product (82) as a colorless oil (100 mg, 19%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:21]=[C:22]([CH2:23][O:24][CH3:33])[C:4]=2[N:3]=1
Reactant: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of [2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazol-4-yl]methanol, prepared as described in Example 43 (160 mg, 0.381 mmol) in N,N-Dimethylformamide (DMF) (15 mL), sodium hydride (30.5 mg, 0.763 mmol) was added in and followed by the addition of methyl iodide (0.048 mL, 0.763 mmol). The reaction was stirred at rt for 3 hours. More sodium hydride (30.5 mg, 0.763 mmol) and methyl iodide (0.048 mL, 0.763 mmol) was added in. The reaction was stirred at rt for another 2 hours then Water (70 mL) was added in. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with Brine (100 mL), dried (MgSO4) and concentrated. The crude was subjected to ISCO purification (0˜2% MeOH/DCM) to give the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 2.54 (s, 3H) 3.00-3.07 (m, 4H) 3.37 (s, 3H) 3.68-3.75 (m, 4H) 4.76 (s, 2H) 5.52 (s, 2H) 6.32 (d, J=7.83 Hz, 1H) 6.88 (m, 2H) 7.25 (s, 1H) 7.60 (d, 1H). MS (ES+) m/e 434.4 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([C:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH:17]=4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].CO.CN(C=O)C.C(O)(=O)C>[C:1]([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc3[nH]cc(C4=CCN(C)CC4)c3cc21
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc3[nH]cc(C4CCN(C)CC4)c3cc21
Reaction time: 42 h

Procedure:
A mixture of 1-acetyl-7-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (D4, 1.10 g, 3.7 mmole), 10% palladium on carbon (0.20 g) in MeOH (50 ml), DMF (10 ml) and glacial acetic acid (0.5 ml) was shaken under hydrogen at 50 psi/344.8 kPa for 42 hours. The mixture was filtered through Celite (Diatomaceous Earth) and the filtrate evaporated to dryness. The residue was dissolved in water (10 ml) and the pH adjusted to 8 with solid potassium carbonate. The precipitate was collected by filtration washed with water and dried in vacuo to leave the title compound as a buff powder (0.60 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:29])[CH:27]=[CH2:28]>>[CH2:31]([O:30][C:26]([CH2:27][CH2:28][N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:21])[CH2:20][CH2:19]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Product: O=C(CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1)OCc1ccccc1
Yield: 45 %

Procedure:
3.5 g (0.01 mol) of 1-cyclopropyl-6,8-difluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are heated under reflux with 4 g of benzyl acrylate for 5 hours. The hot solution is filtered, and the precipitate which separates out is filtered off under suction, washed with ethanol and dried. 2.3 g of 7-[4-(2-benzyloxycarbonyl-ethyl)-piperazin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 132°-135° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:16]P(OCC)(OCC)=O)=[N:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])C.[H-].[Na+].[Cl:27][C:28]1[CH:29]=[C:30]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:31]2[N:32]([C:34]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[C:35]([CH:37]=O)[N:36]=2)[N:33]=1>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:31]2[N:32]([C:34]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[C:35](/[CH:37]=[CH:16]/[C:10]3[CH:9]=[CH:8][C:7]4[C:6]([C:4]([OH:3])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=3)[N:36]=2)[N:33]=1
Reactant: O=Cc1nc2c(N3CCOCC3)cc(Cl)nn2c1-c1cccnc1
Reactant: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2nc(/C=C/c3nc4c(N5CCOCC5)cc(Cl)nn4c3-c3cccnc3)ccc12
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
To a solution of compound 73d (90 mg, 0.26 mmol) in DMF (3 mL) was added NaH (29 mg, 0.72 mmol) in one portion. Compound 73f (88 mg, 0.26 mmol) was then added as a slurry in DMF (1 mL). The reaction mixture was stirred for 10 min, quenched with water (1 mL) and acidified to pH 5 with 10% citric acid. The solid formed was collected by filtration, washed with water (2 mL), diethyl ether (5 mL), and dried under reduced pressure to afford compound 73g (107 mg). Mass spectrum (LCMS, ESI pos.) Calcd. For C27H21ClN6O3: 513.1 (M+H). found 512.8.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[N:42]=[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([C:52]([O:54]C)=[O:53])[CH:45]=3)[C:40]([F:56])=[CH:39][N:38]=2)=[CH:32][C:31]=1[C:57]([O:59]C)=[O:58].[OH-].[Na+]>>[C:57]([C:31]1[CH:32]=[C:33]([NH:36][C:37]2[N:42]=[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([C:52]([OH:54])=[O:53])[CH:45]=3)[C:40]([F:56])=[CH:39][N:38]=2)[CH:34]=[CH:35][C:30]=1[O:29][CH3:28])([OH:59])=[O:58]
Reactant: COC(=O)c1cc(Nc2ncc(F)c(Nc3ccc(OC)c(C(=O)OC)c3)n2)ccc1OC
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(C(=O)O)c3)n2)cc1C(=O)O
Yield: 103.8 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (80 mg, 0.18 mmol) and NaOH (200 mg, 5 mmol) gave N2,N4-bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (80 mg). 1H NMR (DMSO-d6): δ 3.75 (s, 3H), 3.80 (s, 3H), 6.94 (d, J=9.6 Hz, 1H), 7.05 (d, J=9.3 Hz, 1H), 7.78-7.80 (m, 3H), 7.94 (dd, J=9.3 Hz, 1H), 8.04 (d, J=3.6 Hz, 1H), 9.10 (s, 1H, NH), 9.30 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −165.56; LCMS: ret. time: 14.65 min.; purity: 100%; MS (m/e): 428.83 (MH+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH2:7]1>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[CH2:7]1[C:8]2[C:13](=[C:12]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:11]=[CH:10][CH:9]=2)[CH2:14][NH:6]1
Reactant: COc1ccc(CN2Cc3cccc(OCCN(C)C)c3C2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: CN(C)CCOc1cccc2c1CNC2
Yield: 242.4 %

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-4-(2-dimethylamino-ethoxy)-2,3-dihydro-1H-isoindole (170 mg, 0.48 mmol) in trifluoroacetic acid (0.5 mL) and anisole (0.5 mL) was heated at 150° C. under microwave irradiation for 10 minutes. The mixture was diluted with ethyl acetate and extracted twice with water. The combined aqueous extracts were concentrated to give the title compound as a purple oil (240 mg, including residual TFA and/or water). 1H NMR (methanol-d4) 7.42 (1H, t), 7.07 (1H, d), 7.04 (1H, d), 4.64 (4H, br.s), 4.47-4.44 (2H, m), 3.65-3.63 (2H, m), 3.01 (6H, s). MS: [M+H]+ 207.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16].[C:18]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OCC)=[O:31])=[CH:25][CH:24]=1)(=[O:20])[NH2:19]>>[C:18]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:17])[CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[O:31])=[CH:25][CH:24]=1)(=[O:20])[NH2:19]
Reactant: CCOC(=O)Cc1ccc(OCC(N)=O)cc1
Reactant: N#Cc1ccccc1OCC(O)CNCCN
Product: N#Cc1ccccc1OCC(O)CNCCNC(=O)Cc1ccc(OCC(N)=O)cc1

Procedure:
In a similar manner using 2.36 g. of 3-(β-aminoethylamino)-1-(2-cyanophenoxy)-2-propanol and 2.37 g. of ethyl 4-carbamoylmethoxyphenylacetate as starting materials there is obtained 3-β-(4-carbamoylmethoxyphenylacetamido)ethylamino-1-(2-cyanophenoxy)-2-propanol, isolated as its hydrogen oxalate, m.p. 123°-125° C. after crystallisation from ethyl acetate.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[CH2:22](Br)[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[CH2:22]([S:20][C:19]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:21])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: BrCC=Cc1ccccc1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SCC=Cc1ccccc1
Yield: 32.8 %

Procedure:
In the same manner as descsribed in Example 32, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.16 g), 10N NaOH (2 ml), carbon disulfide (912 mg), dimethylsulfoxide (6 ml) and cinnamyl bromide (2.364 g) are reacted and treated. The product is crystallized from ethanol to give the title compound (1.34 g), m.p. 200°-202° C.
Reaction SMILES: C(OC([N:8]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(CC)CC>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH2:19][C@@H:20]([C:21]([OH:23])=[O:22])[NH:8][CH2:9][C:10]2=3)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1Cc2c(c3ccccc3n2Cc2ccc(F)cc2)C[C@H]1C(=O)O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1Cc2c(n(Cc3ccc(F)cc3)c3ccccc23)CN1
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
The acid 3 (18.9 g, 44.5 mmol), 4M HCl in 1,4-dioxane solution (56 mL, 222.7 mmol), and 1,4-dioxane (85 mL) stirred at RT overnight. The reaction diluted with water (200 mL) and neutralized to pH 7 with Et3N. Water (400 mL) was added and the mixture stirred for 30 min. The solid was collected by filtration and washed with water (300 mL) to afford the amino acid 4 (13.0 g, 90%) as a pale yellow powder. 1H NMR (300 MHz, DMSO-d6): δ 8.95 (br s, 1H), 7.48 (d, 1H), 7.39 (d, 1H), 7.14-6.99 (m, 6H), 5.33 (s, 2H), 4.24 (d, 1H), 4.08 (d, 1H), 3.63-3.58 (m, 1H), 3.17-3.10 (m, 1H), 2.86-2.81 (m, 1H); LC-MS [M+H+ 325].
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1>C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of (3-Hydroxy-propyl)-carbamic acid tert-butyl ester (11 mmoles, 1.88 ml) in THF (20 ml) was added to a suspension of sodium hydride 50% grade (23 mmoles, 1.058 g) in THF (20 ml) and stirred at 50° C for 1 hour. Following cooling to 0° C., 4-Chloro-1-fluoro-2-nitro-benzene was added and the mixture stirred at RT overnight. After quenching with water, the organic layer was separated and the aqueous layer was extracted several times with Ethyl acetate. The combined organic layers were washed with water then brine, and dried over sodium sulfate. The crude reaction was purified by flash chromatography to afford [3-(4-Chloro-2-nitro-phenoxy)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl[CH2:16][CH2:17][CH2:18][CH2:19]Br.[I-:21].[Na+]>>[I:21][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [I-]
Reactant: CCOC(=O)CCc1ccccc1O
Reactant: ClCCCCBr
Agent: [Na+]
Product: CCOC(=O)CCc1ccccc1OCCCCI
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield from ethyl 3-(2-hydroxyphenyl)propionate and 4-chlorobutyl bromide according to the procedure of Preparation 36 followed by treatment with sodium iodide; the product was an oil. NMR.
Reaction SMILES: [C:1](CC(O)=O)#[N:2].[CH2:7]([NH:9][C:10]([NH2:12])=[O:11])[CH3:8].C(O[C:17](=[O:19])[CH3:18])(=O)C>>[NH2:2][C:1]1[N:9]([CH2:7][CH3:8])[C:10](=[O:11])[NH:12][C:17](=[O:19])[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(N)=O
Reactant: N#CCC(=O)O
Product: CCn1c(N)cc(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
To a solution of 127.5 g (1.5 mol) cyanoacetic acid and 200 ml of acetic anhydride was added 120 g (1.36 mol) of ethylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling, white crystals were filtered off and washed with ethanol. Yield 153 g (74%) (I). This was stirred in 1 liter of hot water and 160 ml of 2 N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5 N HCl. After cooling, white crystals were filtered off. Yield 100 g (65%) (II) NMR.
Reaction SMILES: S(F)([O:4][C:5](F)(F)[C:6]([I:9])([F:8])[F:7])(=O)=O.[F-].[K+].[CH2:15]([OH:17])[CH3:16]>>[I:9][C:6]([F:8])([F:7])[C:5]([O:17][CH2:15][CH3:16])=[O:4]
Reactant: CCO
Reactant: O=S(=O)(F)OC(F)(F)C(F)(F)I
Agent: [F-]
Agent: [K+]
Product: CCOC(=O)C(F)(F)I
Yield: 74 %

Procedure:
Ethyl iododifluoroacetate (73.4 g, 74% yield) could also be prepared from 2-iodo-1,1,2,2-tetrafluoroethyl fluorosulfate (130.4 g, 0.4 mol), potassium fluoride (23.2 g, 0.4 mol) and ethanol (150 mL) according to the procedure described in Experiment (3a).
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][C:15](=O)COC2C=CC=CC=2)[C:7]1=[O:25])=O.[Cl:27][C:28]([Cl:38])([Cl:37])[CH2:29][O:30][C:31](=[O:36])[CH:32]=[C:33]([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:27][C:28]([Cl:37])([Cl:38])[CH2:29][O:30][C:31](=[O:36])[C:32]([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][CH3:15])[C:7]1=[O:25])=[C:33]([CH3:35])[CH3:34]
Reactant: CC(C)=CC(=O)OCC(Cl)(Cl)Cl
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Reaction time: 1.25 h

Procedure:
A solution of 3.26 g of 2- (3S,4R)-4-(benzthiazol-2-yldithio]-3-methoxy-2-oxoazetidin-1-yl]-3-methyl-crotonic acid 2,2,2-trichloroethyl ester in 36.3 ml of acetic anhydride and 12.4 ml of acetic acid is cooled to -15° and 1.7 g of triphenylphosphine are added. After stirring under nitrogen at the same temperature for 75 minutes, 24.8 ml of pyridine are added to the mixture. After stirring for a further 3 hours at 0°, the reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is purified by chromatography over silica gel with toluene and toluene/ethyl acetate (19:1). IR spectrum (in methylene chloride): characteristic absorption bands at 3.40, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and 11.90 μ.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][O:14]C(=O)C)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+].C(O)(=O)C>CO>[Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Yield: 54.9 %

Procedure:
A solution of N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (41.7 g, 0.154 mol) in anhydrous methanol (415 ml) is stirred under a N2 atmosphere with ice-bath cooling. A solution of sodium methoxide (415 mg, 7.7 mmol) in anhydrous methanol (15 ml) is added and the resulting solution is stirred in the cold for 2 more hrs. Acetic acid (2.2 ml) is then added and the solvents are evaporated in vacuo (i.v.). The residue is taken up in EtOAc (300 ml), washed with H2O (4×75 ml), 5% NaHCO3 (75 ml) and brine, dried with MgSO4 and evaporated i.v. to a clear oil (21.3 g). This material is purified by chromatography on a Baker silica gel column (425 g, packed under EtOAc). After a 100 ml forefraction, 25 ml EtOAc fractions are collected every 2.5 mins. Fractions 41-49 yield starting material and fractions 51-90 afford N-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin- 2-one (19.4 g) as a clear oil: ir (neat) 2.88, 5.73, 5.80, 7.52, 7.67, 7.99, 8.40, 11.95, and 12.18 cm-1 ; nmr (CDCl3) δ0.25 (s, 6), 0.98 (s, 9), 1.82 (m, 2), 2.67 (dd, 1), 3.17 (dd, 1), 3.67 (t, 2), and 3.67 (m, 1); mass spectrum m/e 172.
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=1)=[O:12].[CH3:21][O:22][C:23](=[O:26])OC.Cl.C1C[O:31][CH2:30]C1>CCOC(C)=O>[CH3:21][O:22][C:23](=[O:26])[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[O:31][CH3:30])=[O:12]
Reactant: COC(=O)OC
Reactant: COc1ccc(C(C)=O)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)c1ccccc1OC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Bis-(trimethylsilyl)amine (158.2 mL, 0.750 mol) was dissolved in 150 mL of THF and cooled to −78° C. with the aid of a dry ice/acetone bath. N-butyl lithium (2.5 M in hexane, 300 mL, 0.750 mol) was introduced via cannula into the system and stirred at that temperature for 20 min. 4-methoxy acetophenone (51.20 g, 0.340 mol) was added via a solid addition funnel and stirred at −78° C. for 3 h. Dimethylcarbonate (87.0 mL, 1.02 mol) was added via cannula and the system allowed to stir overnight with warming to room temperature. The solution was acidified with 10% HCl, diluted with 1 liter of EtOAc and washed three times with 400 mL of 10% HCl. The organics were dried over MgSO4, filtered through a silica gel plug and the volatiles removed in vacuum. The title compound was obtained as a viscous brown oil (65.09 g, 91.7%) MS (NH3-DCI) 347.9 (M+H)+.