Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1[C:44]2[CH:43]([C:45](O)=[O:46])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:45]([CH:43]1[C:44]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(C1c2ccccc2-c2ccccc21)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 83.3 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 78 mg (0.562 mmol) of 9-fluorene carboxylic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (241 mg, 82%) is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.58, FD-MS: M+ =619.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[C:9](OC)=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH4+:14].[Cl-].N>CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[C:9]([NH2:14])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)C(O)c1cccc(Br)n1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)C(O)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(6-bromopyridin-2-yl)-2-hydroxyacetate (0.5, g, 2.03 mmol), NH4Cl (0.1, g) and NH3, (4N in MeOH) was shaken at room temperature over night. The solvent was removed under vacuum then added water (5, mL) and CHCl3, (20, mL) The organic layer was concentrated and purified by chromatographed over silica gel with 50% EtOAc in hexanes to yield 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide as a yellow solid (0.2, g, 16%). 1H NMR (600, MHz, DMSO-d6) 7.77, (1H, dd, J=7.8, & 8.4, Hz), 7.58, (1H, d, J=8.4, Hz), 7.51-7.52, (2H, m), 7.35, (1 H, s), 6.23, (1H, d, J=0.5, Hz, —OH), 4.91 (1H, d, J=0.6, Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][Cl:10])=[CH:5][CH:4]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1>C(O)C>[ClH:10].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13]2)=[CH:5][CH:4]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: COc1ccc(C=CCCl)cc1
Solvent: CCO
Product: COc1ccc(C=CCN2Cc3ccccc3C2)cc1
Product: Cl
Yield: 22.9 %

Procedure:
A solution of 0.45 gram of p-methoxycinnamyl chloride and 0.62 gram of isoindoline in 20 milliliters of ethanol is stirred overnight at room temperature. After completion of the reaction, the reaction mixture is concentrated. Chloroform is then added to the residue, and the insolubles are filtered off. The subsequent operations are carried out as in Example 13 to obtain 0.17 gram (yield 37.7%) of N-(p-methoxycinnamyl)-isoindoline hydrochloride as crystals having a melting point of 201°-202° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:6]([OH:7])[C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].C(Br)Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[O:9][CH2:13][O:7][C:6]=2[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: BrCBr
Product: O=[N+]([O-])c1cc(Cl)cc2c1OCO2
Temperature: 140 °C
Yield: 82 %

Procedure:
Under N2 200 g of 5-chloro-3-nitro-catechol is dissolved in 1050 ml DMF. To this solution are added 204 g anhydrous, powdered K2CO3 and 220 ml CH2Br2, while stirring the mixture. The reaction mixture is refluxed for 1 hour (140° C.) and then cooled down to 80° C. After addition of 800 ml water, the mixture is cooled down to room temp. The crystalline product is filtered off and washed successively with 2×600 ml water, 2×250 ml ethanol, and 2×300 ml n-hexane. After drying under reduced pressure at 60° C., the desired product is obtained in a yield of 82%; purity 95%. Equally successful results are obtained in toluene as the solvent instead of DMF, under phase transfer conditions.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](COC)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:31]([C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1)#N>>[CH3:1][O:2][CH2:31][C@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COC[C@@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: COC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 90 %

Procedure:
The title compound II-aj was prepared in 90% yield from 3,3:17,17-bis(ethylendioxy)-6β-methoxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 70/10/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.45 (m, 2H), 3.27 (s, 3H), 2.80-0.80 (m, 21H), 1.10 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3Cl)cc2)cc1
Temperature: 55 °C

Procedure:
The product from Example 24A (75.0 mg, 0.321 mmol), 4-tert-butylaniline (61 μL, 0.383 mmol), PS-DCC (1.35 mmol/g, 0.7132 g, 0.963 mmol), HOBT (44.0 mg, 0.326 mmol), and triethylamine (0.13 mL, 0.93 mmol) in DMF (3 mL) were combined and heated at 55° C. for 16 hours. The mixture was allowed to cool to room temperature, filtered, and the filtrate was diluted with diethyl ether (20 mL). The diethyl ether was washed with 1N HCl (15 mL), brine (15 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.63 (dd, 1H), 7.98 (d, 2H), 7.88 (d, 2H), 7.83 (d, 1H), 7.81 (br s, 1H), 7.59 (d, 2H), 7.41 (d, 2H), 7.29 (dd, 1H), 1.33 (s, 9H); MS (m/z) 365.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH2:53])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1>CN(C=O)C>[NH:37]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N:35]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH:53][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)=[O:15])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1-(Pyridin-4-yl)piperidine-4-carboxylic acid (14 mg, 0.068 mmol), HOBt (12 mg, 0.088 mmol), EDC (17 mg, 0.088 mmol) and sodium bicarbonate (5 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuum. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (12 mg).
Reaction SMILES: [OH:1][C:2]1[C:9]([I:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][C:14](/[C:17](=C\C)/C(OCC)=O)([F:16])[F:15].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>>[I:10][C:9]1[C:8]([O:11][CH3:12])=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][CH:17]([C:14]([F:16])([F:15])[F:13])[C:37]([C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4]2
Reactant: COc1ccc(C=O)c(O)c1I
Reactant: C/C=C(/C(=O)OCC)C(F)(F)F
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(OC)c(I)c2OC1C(F)(F)F
Temperature: 90 °C
Yield: 14 %

Procedure:
To the mixture of 1.5 g (5.4 mmol) of 2-hydroxy-3-iodo-4-methoxybenzaldehyde, 3.1 mL (20.6 mmol) of ethyl trifluoromethylcrotonate, and 4.2 g(12.9 mmol) of cesium carbonate was added 8 mL of anhydrous N,N-dimethylformamide. The mixture was heated to 90° C. overnight. After cooling to room temperature, to the reaction was added 150 mL of ethyl acetate. The organic solution was filtered, washed with brine and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified by silica chromatography with ethyl acetate/hexane (2:8) to give 0.3 g (14%) a light yellow solid: 1H NMR(CDCl3/400 MHz) 7.65(s, 1H), 7.17(d, J=8.4 Hz, 1H), 6.50(d, J=8.4 Hz, 1H), 5.80(q, J=6.8 Hz,1H), 4.30(m, 2H), 3.92(s, 3H), 1.33(t, J=7.6 Hz, 3H). MS (ESI+) 429.0(M+1, 100). HRMS (EI+) m/z calcd for (C14H12F3O4) 427.9732, found 427.9715.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1>>[O:21]1[CH:22]=[CH:23][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:24])[CH:13]=2)=[CH:20]1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CBr)cc1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccoc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(Furan-3-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 5.1c from 150 mg (85% purity, 0.33 mmol) 1-[2-(4-bromomethylphenyl)-ethyl]-4-(furan-3-ylmethoxy)-1H-pyridin-2-one (example 5.1b) and 187 mg (1.31 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[C:16]3[C:17]4([CH2:20][O:21][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:18]4)=[N:8][CH:9]=1)([O-])=O.O.[Cl-].[NH4+]>O1CCCC1>[C:17]12([C:16]3[C:11]([O:10][C:7]4[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[O:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of 5-nitro-2-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)pyridine (Reference Intermediate 215, 99 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (97 mg, 1.741 mmol) and then ammonium chloride (93 mg, 1.741 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound as a light yellow solid (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15](Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
1-(4-Methoxyphenyl)cyclopropanecarboxylic acid (0.970 g, 5.05 mmol) in dichloromethane (DCM; 5 mL) was mixed with oxalyl chloride (1.28 mL, 15.1 mmol) followed by addition of a drop of N,N-dimethylformamide (DMF; 20 μL). The mixture was stirred at room temperature (RT) for 2 h. The solvent was evaporated. The residue was co-evaporated with toluene (2×), and dissolved in DCM (10 mL). The solution was cooled at −10° C., and then methanol (3 mL) was carefully added to the solution. The resulting mixture was allowed to warm to RT. The volatiles were evaporated under reduced pressure to afford the desired product (1.03 g, 99%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br.[C:28]1([N:34]2[CH2:38][CH2:37][N:36]=[C:35]2[NH2:39])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:11]([O:18][C:19]1[C:20](=[O:22])[N:36]2[CH2:37][CH2:38][N:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:35]2=[N:39][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC1=NCCN1c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)COCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2c1ccccc1
Yield: 10.5 %

Procedure:
Reaction of the adduct of diethyl oxalate (7.06 g, 48.3 mmol), ethyl benzyloxyacetate (9.38 g, 48.3 mmol) and sodium hydride (2.12 g of a 60% dispersion in mineral oil, 53.1 mmol) with 1-phenyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (11.70 g, 48.3 mmol) as described for intermediate 1 gave 1.99 g (11% yield) of the title ester as white crystals; mp 132-134° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH3), 4.23-4.29 (4H, m, 2×CH2), 4.35 (2H, q, J=7.1 Hz, OCH2), 5.18 (2H, s, OCH2), 7.16 (1H, m, aromatic), 7.3-7.53 (7H, m, aromatics), 7.73 (2H, m, aromatics). Anal. Calcd for C22H21N3O4: C, 67.50; H, 5.40; N, 10.73. Found: C, 67.44; H, 5.68; N, 10.73.
Reaction SMILES: [N:1]1([CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][C@@H:27]4[CH2:31][CH2:30][O:29][CH2:28]4)=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:32][N:33]([CH3:37])[C:34]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24]([O:26][C@@H:27]5[CH2:31][CH2:30][O:29][CH2:28]5)=[O:25])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:35]
Reactant: O=C(O[C@@H]1CCOC1)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Reaction time: 0.17 h

Procedure:
(R)-tetrahydrofuran-3-yl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.047 mmol) was dissolved in CH2Cl2 (1 mL) and treated with a solution of dimethylcarbamic chloride (20 mg, 0.13 mmol) in CH2Cl2 (100 μL). A solution of diisopropyl ethylamine (20 μL, 14.8 mg, 0.11 mmol) was added. The resulting mixture was allowed to stand at room temperature for 10 min and was then purified by LC/MS (10-99% CH3CN—H2O, with 0.03% TFA, 9 min) to provide (R)-tetrahydrofuran-3-yl 3-(2-(dimethylcarbamoyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 497.4, retention time 2.15 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: C(OC([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:42])[C:16]([NH:18][CH:19]2[C:40](=[O:41])[N:21]3[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]4[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=4)[CH2:24][S:25][C@H:20]23)=[O:17])[N:14]=1)=O)(CC)(C)C>C(O)=O>[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:42])[C:16]([NH:18][CH:19]2[C:40](=[O:41])[N:21]3[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]4[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=4)[CH2:24][S:25][C@H:20]23)=[O:17])[N:14]=1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=O)O)CS[C@H]23)cs1
Solvent: O=CO
Product: Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=O)O)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 33.6 %

Procedure:
A mixture of 7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (870 mg.) and 99% formic acid (16 ml.) was stirred for 3.5 hours at ambient temperature. The solvent was distilled off and to the residue was added diethyl ether (20 ml.). Insoluble material was collected by filtration and dissolved in 5% sodium bicarbonate aqueous solution (20 ml.) the aqueous solution was washed with ethyl acetate (20 ml.) and to the resulting aqueous solution was added ethyl acetate (60 ml.). The mixture was adjusted to pH 2.0 and 10% hydrochloric acid with stirring to precipitate powder. The precipitates were collected by filtration, well stirred in ethyl acetate (50 ml.) to remove impurities and collected by filtration to give 7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (240 mg.). The aqueous layer in the filtrate of pH 2.0 as mentioned above was separated and allowed to stand overnight. Precipitates were collected by filtration further to give the same object compound (120 mg.). Total yield 360 mg.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32]C(OC)=O)=[CH:27][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1.O.[ClH:38]>CO>[ClH:38].[F:3][C:4]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCn1ccnc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2M Aqueous sodium hydroxide (0.3 ml, 6 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (257 mg, 5.5 mmol) in methanol (5 ml) and the mixture stirred for 1 hour at 40° C. Water and 1M hydrochloric acid (0.6 ml) were added and the mixture concentrated to half volume by evaporation. The resulting solid was collected by filtration, dissolved in methylene chloride/methanol and a solution of 7M hydrogen chloride in isopropanol (0.4 ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (160 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])C=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][C:31]2[C:39]([O:38][CH3:37])=[CH:44][CH:43]=[CH:42][C:41]=2[O:45][CH3:46])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cccc(OC)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4c(OC)cccc4OC)cc3C)c2cc1OC
Yield: 96.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2,6-dimethoxyphenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (75 mg, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[C:21]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl>C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cccc(F)c4Cl)CC3)c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (41, 125 mg, 0.27 mmol) in CH2Cl2 (2 mL) was added HCl (2.0 N solution in Et2O, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to give (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride as a white solid (42, 93 mg, 86%): 1H NMR (300 MHz, DMSO-d6) δ 9.37 (br s, 2H), 7.42-7.21 (m, 3H), 5.31-5.13 (m, 1H), 4.74-4.57 (m, 1H), 4.25-4.14 (m, 2H), 3.44-3.14 (m, 4H, overlaps with H2O), 3.00-2.75 (m, 3H), 1.93-1.77 (m, 2H), 1.70-1.47 (m, 2H) missing N—H pyrazole; ESI MS m/z 363 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])Cl)=[C:6]([F:14])[C:5]=1[I:15]>C1COCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:2][CH3:1])=[N:10][OH:11])=[C:6]([F:14])[C:5]=1[I:15]
Reactant: CN
Reactant: ON=C(Cl)c1ccc(Cl)c(I)c1F
Solvent: C1CCOC1
Product: CNC(=NO)c1ccc(Cl)c(I)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (33% wt solution in absolute ethanol, 1.9 mL, 18 mmol) was added dropwise to a solution of 4-chloro-2-fluoro-3-iodobenzoyl chloride oxime (0.600 g, 1.8 mmol) in anhydrous THF (10 mL) at 0° C. The reaction mixture was stirred at RT for 1 h. The volatile solvents were removed under reduced pressure. Flash chromatography on silica gel (dichloromethane:hexane 25:75) gave 4-chloro-2-fluoro-N′-hydroxy-3-iodo-N-methylbenzamidine as an amorphous white solid. MS (ESI, pos.ion) m/z: 330.9 (M+1)