Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[C:17]([Cl:28])[CH:16]=1.[CH2:29]1C[O:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:31](=[O:32])[CH:30]=[CH2:29])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1
Reactant: C1CCOC1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc(N)cc23)cc1Cl
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved most of 1.00 g (2.46 mmol) 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-quinoline-3-carbonitrile in 3.5 ml hot DMF, added 12 ml THF and chilled to 0° C. Added 377 μl triethyl amine and 225 μl (2.70 mmol) acryloyl chloride. Removed ice bath at 15 minutes and stripped solvent at 2 hours. Slurried residue in water, collected solids and air dried overnight. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 670 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=461.1, 462.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:22]([N:16]1[CH2:17][CH:6]2[CH:7]([C:2]([CH3:9])([CH3:1])[CH:3]=[CH:4][C:5]2=[O:8])[CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)C=CC(=O)C=C1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C=CC(=O)C2CN(Cc3ccccc3)CC21

Procedure:
To a solution of 15.96 g of 4,4-dimethyl-2,5-cyclohexadienone and 46 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 200 cm3 of dichloromethane are added, at a temperature of 10° C., 8 drops of trifluoroacetic acid. The reaction mixture is brought to reflux for 2 hours and potassium carbonate is then added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8.5 cm, height 30 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 100 cm3 fractions. Fractions 38 to 56 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 14.7 g of (3aRS,7aRS)-2-benzyl-7,7-dimethyl-2,3,3a, 4,7,7a-hexahydro-1H-4-isoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([C:4](N)=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C.CO>[CH:1]1([C:4]2[N:29]([C@@H:30]3[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]3)[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)C1CC1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: OC[C@H]1CC[C@H](n2c(C3CC3)nc3cnc4ccsc4c32)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclopropanecarboxamide (72.6 mg, 0.853 mmol) and triethyloxonium tetrafluoroborate (0.161 g, 0.845 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.48 mL) and added to a suspension of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (72.0 mg, 0.258 mmol) in ethanol (1.8 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C17H20N3O2S (M+H)+: m/z=330.1. Found: 330.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[O:17])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Reactant: CCOC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.26 mmol) in 10 ml of anhydrous THF were added HATU (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol). The mixture was heated at 60° C. for 5 minutes, followed by addition of ethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate as white solid. Yield: 150 mg, 100%.
Reaction SMILES: C(OC(=O)C1C=CC(N2CCC(N[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)C2)=CC=1)(C)(C)C.C(OC(=O)C1C=C[C:35]([N:38]2[CH2:42][CH2:41][C:40](=O)[CH2:39]2)=CC=1)(C)(C)C.[NH2:45]C1C=NC=CC=1>>[N:38]1[C:35]([NH2:45])=[CH:39][CH:40]=[CH:41][C:42]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(Nc3cccnc3)C2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(=O)C2)cc1
Product: Nc1cccc(-c2cccnc2)n1
Yield: 76 %

Procedure:
The title compound 204 was obtained following the procedure as for the reductive amination described in scheme 3, step 2 (example 12) starting from compound 203 and using 3-aminopyridine instead of 6-(pyridin-3-yl)pyridin-2-amine (11) (76% yield). 1H NMR: (acetone-d6) δ (ppm): 8.08 (d, J=2.7 Hz, 1H), 7.85 (dd, J=4.3, 1.6 Hz, 1H), 7.79 (d, J=9.0 Hz, 2H), 7.09 (ddd, J=8.2, 4.5, 0.8 Hz, 1H), 7.06 (ddd, J=8.2, 2.7, 1.6 Hz, 1H), 6.58 (d, J=9.0 Hz, 2H), 4.33 (quint, J=4.9 Hz, 1H), 3.79 (dd, J=10.2, 6.1 Hz, 1H), 3.60-3.54 (m, 1H), 3.51-3.45 (m, 1H), 3.32 (dd, J=7.2, 4.1 Hz, 1H), 2.44 (sext., J=7.6 Hz, 1H), 2.18-2.11 (m, 1H), 1.56 (s, 9H). m/z: 340.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:12]([OH:14])=O.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>>[F:16][C:17]1[CH:18]=[C:19]([NH:20][C:12]([C@H:3]2[C@H:4]([C:5]3[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)[C:2]2([CH3:1])[CH3:15])=[O:14])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Cc1cccc([C@H]2[C@H](C(=O)O)C2(C)C)c1
Product: Cc1cccc([C@H]2[C@H](C(=O)Nc3ccc(F)c(F)c3)C2(C)C)c1
Yield: 92 %

Procedure:
trans-2,2-Dimethyl-3-m-tolyl-cyclopropanecarboxylic acid (2.04 g, 10 mmol) and 3,4-difluoroaniline (1.29 g, 10 mmol) were reacted as described under General Procedure D to furnish the title compound (2.9 g, 92%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.70-7.64 (m, 1H), 7.47 (s, 1H), 7.20-6.96 (m, 6H), 2.79 (d, J=5.6 Hz, 1H), 2.33 (s, 3H), 1.80 (d, J=5.6 Hz, 1H), 1.40 (s, 3H), 0.97 (s, 3H). mp 110-113° C. ESIMS m/z [M+H]+ 316.2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:36]3[CH:40]=[N:39][N:38]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1-c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cnn(Cc4cccc(Cl)c4)c3)c(C(=O)O)n1)CC2
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 9B (0.178 g), 1-(bromomethyl)-3-chlorobenzene (0.080 g) and cesium carbonate (0.170 g) was stirred together in N,N-dimethylformamide (2 mL) at room temperature. After 3 hours, the reaction was diluted with ethyl acetate (25 mL) and washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane (1 mL) and treated with TFA (1 mL) and stirred overnight. The mixture was concentrated, dissolved in dichloromethane and loaded onto silica gel and eluted using a gradient of 0.5% to 4% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.84 (s, 1H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.60 (dd, 2H), 7.53-7.28 (m, 7H), 7.22-7.16 (m, 1H), 6.95 (d, 1H), 5.35 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)[CH:12]=[CH:11][N:10]1[CH2:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2C(OC(C)(C)C)=O)=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+].CC#N>ClCCl>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([CH2:28][N:10]3[CH:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[N:16]=4)=[CH:14][C:9]3=[O:8])[CH:37]=2)[CH:33]=[CH:34]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Cn3ccc(-c4ccnc(NC5CCOCC5)n4)cc3=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (70 mg, 0.14 mmol) in dichloromethane (3 mL) at 20° C. The mixture was stirred at room temperature for 2 hours. LC-MS showed the tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate had disappeared. The reaction mixture was adjusted with a saturated NaHCO3 solution to a pH of around 8-9, then extracted with dichloromethane, and dried with Na2SO4. The organic phase was evaporated, and the residue was purified with prep-HPLC (A: H2O including 0.5% NH3HCO3, B: CH3CN) to afford 1-((1H-indol-6-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (11 mg, 20% yield). 1H NMR (500 MHz, (CD3)2SO) δ 11.10 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.40-7.32 (m, 3H), 7.15-7.11 (m, 2H), 7.03 (d, J=8 Hz, 1H), 6.85 (d, J=7 Hz, 1H), 6.39 (s, 1H), 5.22 (s, 2H), 3.98 (m, 1H), 3.89-3.85 (m, 2H), 3.45-3.36 (m, 2H), 1.86-1.83 (m, 2H), 1.60-1.45 (m, 2H); LCMS (ESI) m/z: 402.2 [M+H+].
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([OH:24])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of n-butyllithium (2.0 M in hexanes, 3.45 mL, 7.5 mmol) (Aldrich) in tetrahydrofuran (3 mL) at −78° C. was added a solution of 3-bromo-pyridine (0.96 g, 8.1 mmol) (Aldrich) in tetrahydrofuran (6 mL) dropwisely. After the addition, the resulting dark solution was stirred for additional 15 minutes. A solution of 6-chloroisatin (0.5 g, 2.76 mmol) (Crescent) in tetrahydrofuran (5 mL) was added dropwisely and the crude was warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was quenched with water. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-6-Chloro-3-hydroxy-3-pyridin-3-yl-1,3-dihydro-indol-2-one as a yellow solid. (Yield 0.27 g, 37%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[C:15]2[N:16]=[C:17]([N:19]3[CH2:22][CH:21]([NH:23]C(=O)OC(C)(C)C)[CH2:20]3)[O:18][C:14]=2[C:13]([N:31]2[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32]2)=[C:12]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]=1[CH3:45])#[N:9].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:8]([C:10]1[C:15]2[N:16]=[C:17]([N:19]3[CH2:22][CH:21]([NH:23][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:20]3)[O:18][C:14]=2[C:13]([N:31]2[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32]2)=[C:12]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]=1[CH3:45])#[N:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(NS(C)(=O)=O)C3)nc2c1C#N
Yield: 20.2 %

Procedure:
With cooling with ice, trifluoroacetic acid (1 ml) was added to a dichloromethane (2 ml) solution of tert-butyl (1-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}azetidin-3-yl)carbamate (I-195) (77.6 mg, 0.15 mmol), followed by stirring with cooling with ice for 1 hour. The reaction liquid was concentrated under reduced pressure, dissolved in dichloromethane (2 ml), and with cooling with ice, triethylamine (210 ml, 1.52 mmol) and methanesulfonyl chloride (25.6 μl, 0.33 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), and washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1) to obtain the entitled compound (15.0 mg, 19.7%) as a colorless solid.
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.[CH:28]([N:31]1[CH2:35][CH2:34][N:33]=[C:32]1[NH2:36])([CH3:30])[CH3:29]>>[CH2:11]([O:18][C:19]1[C:20](=[O:22])[N:33]2[CH2:34][CH2:35][N:31]([CH:28]([CH3:30])[CH3:29])[C:32]2=[N:36][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: CCOC(=O)COCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)N1CCN=C1N
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2C(C)C
Yield: 38.2 %

Procedure:
Reaction of the adduct of diethyl oxalate (7.26 g, 49.7 mmol), ethyl benzyloxyacetate (9.65 g, 49.7 mmol) and sodium hydride (2.19 g of a 60% dispersion in mineral oil, 54.7 mmol) with 1-isopropyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (10.33 g, 49.7 mmol) as described for intermediate 1 gave 6.79 g (38% yield) of the title ester as white crystals; mp 131-132° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.22 (6H, d, J=6.8 Hz, 2×CH3), 1.31 (3H, t, J=7.1 Hz, CH3), 3.66 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.31 (2H, q, J=7.1 Hz, OCH2), 4.40 (1H, m, CH), 5.08 (2H, s, OCH2), 7.3-7.39 (3H, m, aromatics), 7.49 (2H, m, aromatics). Anal. Calcd for C19H23N3O4: C, 63.85; H, 6.48, N 11.75. Found: C, 63.57; H, 6.76; N, 11.98.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.ClN1[C:45](=[O:46])CCC1=O>CO>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:46][CH3:45])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmol) in 40 ml of methanol and 60 ml. of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2X), dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (mp 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl3 ) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H) 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic and N--H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.O=S(Cl)Cl.[OH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:39]3[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: OCCN1CCNCC1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CC=C(c2cc(C(C)(C)N3CCN(CCO)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in the previous step, 50.0 mg, 0.132 mmol) in 2 mL of DCM at −15° C. was added SOCl2 (29 μL, 0.40 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled back to −15° C. To the reaction was added 2-hydroxylethylpiperazine (162 μL, 1.32 mmol). After stirring at −15° C. for 1 h, the resulting mixture was warmed to RT and stirred for 16 h under Ar. Treated with EtOAc (30 mL), the mixture was washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (2-6% MeOH/DCM) to afford the title compound (37.5 mg, 58%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 1H, J=8.6 Hz), 7.93 (s, 1H), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.34 (d, 1H, J=2.3 Hz), 5.72 (m, 1H), 3.70 (t, 2H, J=6.1 Hz), 2.52-2.77 (m, 10H), 2.25-2.32 (m, 2H), 2.04-2.10 (m, 2H), 1.59 (t, 2H, J=6.2 Hz), 1.38 (s, 6H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H38N6O2, 491.3 (M+H). found 491.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]([C:22]1[CH2:27][NH:26][CH2:25][CH2:24][CH:23]=1)=[O:21].Br.C(N(C(C)C)CC)(C)C.CN(C)[CH:40]=[O:41]>C1(C)C=CC=CC=1>[C:40]([OH:41])(=[O:2])[C:20]([OH:19])=[O:21].[CH3:18][O:19][C:20]([C:22]1[CH2:27][N:26]([CH2:12][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)[CH2:25][CH2:24][CH:23]=1)=[O:21]
Reactant: COC(=O)C1=CCCNC1
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)CC2
Reactant: CN(C)C=O
Agent: Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CC2CCc3ccc(OC)cc32)C1
Product: O=C(O)C(=O)O
Reaction time: 24 h

Procedure:
5.13 g (20 mmol) of methanesulphonic acid (6-methoxyindan-1-ylmethyl) ester are dissolved in 20 ml of toluene and added to a solution of 4.9 g (22 mmol) of guvacoline hydrobromide in 15 ml of dimethylformamide and 5.65 g (44 mmol) of N,N-diisopropyl-N-ethylamine. The reaction mixture is stirred at 50° under nitrogen for 24 hours. The solvents are then substantially removed under reduced pressure. The residue is dissolved in 2N hydrochloric acid, the acidic solution is extracted by shaking with diethyl ether and the ethereal phases are separated off. The acidic aqueous solution is rendered basic with saturated sodium bicarbonate solution and extracted with diethyl ether. The ethereal solutions are subsequently washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation in vacuo. The resulting residue is purified on silica gel with dichloromethane/methanol (19:1) and the resulting eluates are concentrated to dryness by evaporation. The resulting 1-[(6-methoxyindan-1-yl)methyl]-1,2,5,6-tetrahydro-pydridine-3-carboxylic acid methyl ester is dissolved in diethyl ether and oxalic acid is added thereto. The oxalate which precipitates is recrystallised from isopropanol/water and from diethyl ether. 1-[(6-methoxyindan-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester oxalate of m.p. 184°-186° is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14](Cl)(=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CO.C(Cl)(Cl)Cl>[OH-].[Na+].O1CCCC1>[CH3:1][N:2]([CH2:3][C@H:4]([OH:5])[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@H:10]([OH:11])[CH2:12][OH:13])[C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 1 h
Yield: 29.4 %

Procedure:
N-Methyl glucamine (1.95 g, 10.0 mmol) was dissolved in 10 mL of 1.00 N sodium hydroxide solution and 10 mL of tetrahydrofuran. Docosanoyl chloride (3.58 g, 10.0 mmol) was then added to the rapidly stirred solution followed by another 20 mL portion of tetrahydrofuran. After stirring for 60 min, the thick reaction mixture was placed on a rotary evaporator and tetrahydrofuran was removed under reduced pressure. The resulting thick slurry was filtered, washed with water and dried with suction to give a waxy white solid. Chromatography (SiO2, 15%-30% MeOH/CHCl3) yielded 1.52 g of the following compound as a waxy solid.