Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[CH:35][C:20]([O:21][S:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=3)(=[O:24])=[O:23])=[C:19]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:42](OC(=O)C)(=[O:44])[CH3:43].[I-].[Mg+2].[I-]>>[C:42]([O:34][C:27]1[CH:26]=[C:25]([S:22]([O:21][C:20]2[CH:35]=[CH:36][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:24])=[O:23])[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])(=[O:44])[CH3:43]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C4CCCC4)c3)c2c1C
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C2CCCC2)ccc1C(=O)O
Yield: 78.5 %

Procedure:
Using 4-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.293 g, 0.450 mmol), acetic anhydride (3.6 mL, 38.2 mmol) and magnesium iodide (0.125 g, 0.450 mmol) the tidle compound was prepared according to the procedure in Example 5. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 10 & 30% EtOAc/pet. ether step gradient gave 0.245 g (79%) of the title compound as a colorless solid, mp 155-167° C.; 1H NMR (DMSO-d6) δ 1.32-1.38 (m, 2 H), 1.49-1.53 (m, 5 H), 1.58-1.63 (m, 3 H), 1.78-1.80 (m, 1 H), 2.30 (s, 3 H), 2.45 (s, 3 H), 3.00-3.28 (m, 1 H), 7.25-7.29 (m, 2 H), 7.36-7.39 (m, 2 H), 7.50 (t, 1 H), 7.67 (t, 1 H), 7.83 (d, b 1 H), 7.93 (dd, 1 H), 8.19-8.22 (m, 2 H), 13.6-13.8 (br. s, 1 H). mass spectrum (-ESI), m/z 691/693 (M-H). Anal. Calcd. for C34H29BrO7S2.0.3H2O: C, 58.42; H, 4.27 N, 0.00. Found: C, 58.38; H, 4.55 N, 0.10.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCC(F)(F)F)nc1
Temperature: 200 °C
Yield: 43.1 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol), 2,2,2-trifluoro-ethylamine (940 mg, 9.45 mmol) and N,N-diisopropylethylamine (1.64 mL, 9.45 mmol) in 1-methyl-pyrrolidin-2-one (10 mL) in a sealed tube was heated by microwave at 200° C. for 10 minutes. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (Isco 120 g column, 40% ethyl acetate/hexanes) to give (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (300 mg, 43%) as a yellow solid. LCMS calcd for C7H6F3N3O2 (m/e) 221, obsd 222 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:17]=[C:16]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+].Cl>C1COCC1>[CH3:14][N:10]([CH2:11][CH2:12][CH3:13])[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([CH:17]=[C:16]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[CH:15]=1)[C:4]([OH:24])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(-c2nc(C)no2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2nc(C)no2)c1

Procedure:
Stir a solution of N-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-N-propyl-isophthalamic acid ethyl ester (135 mg, 0.4 mmol), 1 N lithium hydroxide (1.6 mL, 1.6 mmol) and THF (1.6 mL) at room temperature overnight. Add 1 N HCl (20 mL) and extract with ethyl acetate (3×20 mL). Dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: C([O:5][NH:6][C:7]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])=[O:8])(C)(C)C>ClCCCl>[OH:5][NH:6][C:7]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:19][CH2:20][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)(=[O:17])=[O:16])=[O:8]
Reactant: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCCl
Product: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
A solution of N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (100 mg, 0.22 mmol), [prepared as described in Step 1 above], in 1,2-dichloroethane (10 ml) was cooled to -30° C. and HCl gas was bubbled through it for 10 min. The reaction vessel was then sealed and stirred at RT. After 2 days, the reaction mixture was vented with nitrogen and then concentrated in vacuo. The residue was chromatographed (PTLC, SiO2, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (51%), mp 84.4-86.4° C.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[C:58]([CH3:59])=[CH:57][CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[CH3:52][C:53]1[C:58]([CH3:59])=[CH:57][CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1cccc(NC2CCNCC2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.097 g, 0.00036 mol) in DMF (1 mL) was added DIPEA (0.233 g, 0.00180 mol), HOBt (0.053 g, 0.00036 mol) and EDCI.HCl (0.138 g, 0.00072 mol) at ambient temperature. After 2 minutes (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.12 g (77%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,3-dimethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 432.23 (M+1)+, 95.88%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.1 (s, 1H), 7.8 (t, 2H), 7.6 (m, 3H), 7.1 (s, 1H), 6.9 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.4 (m, 2H), 4.2 (s, 2H), 3.9 (d, 1H), 3.5 (s, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.2 (s, 3H), 2.0 (s, 5H), 1.4 (m, 2H).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20](Br)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:28]([S:30]SCC)[CH3:29].C([O-])(=O)C.[NH4+]>O1CCCC1.CO.O>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([S:30][CH2:28][CH3:29])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCSSCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A solution of n-butyl lithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) in tetrahydrofuran (5 mL) was stirred at −78° C. for 5 min. under an argon atmosphere. A mixture of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (0.2 g, 0.54 mmol) in tetrahydrofuran (5 mL) was added dropwise, maintaining the temperature below −70° C. The resultant dark red solution was left to stir at −78° C. for 30 min then ethyl disulfide (0.13 mL, 1.08 mmol) was added. The mixture was left to stir at −78° C. for 2 h, then left to warm to room temperature over 2 h. Water (1 mL) was added and the mixture was poured onto an isolute HM-N SPE cartridge and eluted with ethyl acetate (10 mL). The eluent was evaporated under reduced pressure and the crude material was purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 mm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to give the title compound (0.071 g, 53% yield) as a pale yellow oil: m/z M+ 350.14 (M+1); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 mL/min) 6.21 min.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-tert-butyloxybenzoate (16.7 g, 80 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (4.55 g, 120 mmol) by small portions under ice-cooling. The mixture was stirred at room temperature for 1 hr. and water (10 ml) was added under ice-cooling to allow decomposition. Insoluble material was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give the objective substance (12.8 g, 88%) as an oil.
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:38])[CH2:21][CH2:20]2)[CH:14]=1.[H][H]>CO.[Pd]>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:28]2[NH:27][C:26](=[O:38])[N:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:15]4[CH:14]=[C:13]([O:12][C:3]5[CH:4]=[CH:5][C:6]6[NH:7][C:8]([CH3:11])=[N:9][C:10]=6[CH:2]=5)[N:18]=[CH:17][N:16]=4)[CH2:20][CH2:21]3)[CH2:31][CH2:30][C:29]=2[CH:32]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(C)nc5c4Cl)ncn3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(C)nc5c4)ncn3)CC1)C(=O)N2

Procedure:
90 mg (0.17 mmol) 3-(1-(6-(4-chloro-2-methyl-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one and 0.10 mL (0.71 mmol) TEA were placed in 10 mL methanol and hydrogenated under hydrogen atmosphere and with the addition of 10 mg Pd/C (10%) at 50° C. and a hydrogen pressure of 3 bar until the uptake of hydrogen had ended. The catalyst was filtered off and the filtrate was evaporated down i.vac. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:20])=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)(=[O:23])C.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:20]=[O:23])=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)c2ccccc2)c1C
Reactant: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C=O)c(C(=O)c2ccccc2)c1C
Yield: 75 %

Procedure:
A mixture of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.13 g, 15.2 mmol) and ceric ammonium nitrate (33 g, 4 equiv.) in 50 mL of tetrahydrofuran (THF):acetic acid (HOAc):H2O 1:1:1 was refluxed overnight. The reaction mixture was then cooled, extracted with EtOAc and then basified to pH 9 with sodium carbonate. The organic layer was then washed with brine, dried (MgSO4) and concentrated followed by column chromatography to give 3.25 g (75%) of 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]O)[CH:25]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:25]=1)[CH3:15]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CCc1cccc(CC)c1-c1cccc(CO)c1
Product: CCc1cccc(CC)c1-c1cccc(COc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and (2′,6′-diethylbiphenyl-3-yl)methanol. a yellow oil (yield 80%).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1)=[CH2:2].[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>C(O)C>[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:2][CH2:1][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC1CCCN1
Reactant: C=Cc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Solvent: CCO
Product: CC1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Yield: 99.6 %

Procedure:
A solution of 24.6 mg (0.1 mmol) of 4-(2-vinyl-benzooxazol-5-yl)-benzonitrile and 24 mg of racemic 2-methyl-pyrrolidine (Aldrich, CAS #765-38-8) in 0.25 mL of ethanol was stirred at room temperature for 1 hour, then concentrated in vacuo to a glass to give pure product racemic 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzooxazol-5-yl}-benzonitrile 33 mg (100%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.50 (dd, J=7.5, 1.8 Hz), 3.2-3.32 (m, 4H), 1.44-2.65 (m, 7H), 1.15 (m, 3H); Mass spectrum: [M+H]+ 332.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[N:11]=[C:10](C(Cl)(Cl)Cl)[O:9][N:8]=1.[NH3:16]>CCOCC>[NH2:16][C:10]1[O:9][N:8]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: ClC(Cl)(Cl)c1nc(Cc2cccs2)no1
Reactant: N
Solvent: CCOCC
Product: Nc1nc(Cc2cccs2)no1

Procedure:
124.8 g. (0.44 moles) of the 3-(2-thienylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole obtained in part (a) are dissolved in 100 ml. of ether and added dropwise to 200 ml. of liquid ammonia at -45° with stirring. This mixture is stirred for one more hour and then the ammonia and solvent are permitted to evaporate overnight. The solid residue is treated with water and filtered under suction. 75 g. of crude 5-amino-3-(2-thienylmethyl)-1,2,4-oxadiazole are obtained which is recrystallized from isopropanol, yield 52.5 g., m.p. 132°-133°.
Reaction SMILES: [OH-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[NH:21][C:22]=2[CH:23]=1>O.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[N:21]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:22]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(Br)ccc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
6 N NaOH (10 mL), TsCl (0.48 g, 2.5 mmol) and (Bu4NH)2SO4 (50% solution in water, 0.17 mL) were added to a solution of tert-butyl 8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.76 g, 2.1 mmol) in toluene (17 mL), and the resulting solution was stirred for 18 h. Additional TsCl (55 mg, 0.29 mmol) was added, and the reaction was stirred for 18 h. The solution was partitioned with H2O and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO hexanes/EtOAC, 90:10 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes) provided the title compound (0.54 g, 50%) as a white foam: 1H NMR (500 MHz, DMSO-d6) δ 8.24-8.20 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H) 4.44-4.40 (m, 2H), 3.56 (t, J=5.5 Hz, 2H), 3.20-3.18 (m, 2H), 2.31 (s, 3H), 1.86-1.84 (m, 2H), 1.29-1.03 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([O:26][CH2:27][CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][N:15](CC3C=CC=CC=3)[C:14]2=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1([Li])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([O:26][CH2:27][CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][NH:15][C:14]2=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(Cn1ccn(Cc2ccccc2)c1=O)c1ccc(OC)c(OC)c1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(Cn1cc[nH]c1=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.7 %

Procedure:
A solution of (±)-1-[2-(3,4-dimethoxyphenyl)-2-ethoxyethyl]-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-one (4.86 g) in THF (100 ml) was stirred at RT. Phenyllithium (1.278 g) was added dropwise and the mixture was stirred overnight at RT. The mixture was carefully poured out into ice/water (200 ml), then extracted three times with CH2Cl2 (150 ml). The separated organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2(CH3OH/NH3)95/5). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from ethylacetate. The precipitate was filtered off, washed with ethylacetate and DIPE, then dried, yielding 0.1 g (3%) of (±)-1-[2-(3,4-dimethoxyphenyl)-2-ethoxyethyl]-1,3-dihydro-2H-imidazol-2-one (comp. 15; mp. 133.6° C.).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH2:4][S:5](=O)[C@@H:6]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].Cl[Sn]Cl.C(Cl)(=O)C.O>CC#N.CN(C=O)C>[F:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10]
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CF)CS(=O)[C@H]12
Agent: Cl[Sn]Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CF)CS[C@H]12
Reaction time: 1 h

Procedure:
To a solution of 0.494 g (1.0 mmole) of 2,2,2-trichloroethyl 3-fluoromethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 5 ml CH3CN and 2 ml DMF at 0° is added 0.207 g (1.1 mmole) anhydrous SnCl2 and 0.40 g (5 mmole) acetyl chloride and the resulting mixture is stirred at 0° for 1.0 hrs, then at 25° for 1.0 hour, and then poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with 3% HCl solution, 5% NaHCO3 solution, and water, and then dried (MgSO4) and stripped in vacuo to give 2,2,2-trichloroethyl 3-fluoromethyl-7-phenylacetamido-3-cephem-4-carboxylate, which can be purified by chromatography on silica gel with chloroform.
Reaction SMILES: [OH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl>[OH-].[Na+].O1CCCC1>[CH2:15]([O:14][C:12]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1(O)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude 4-hydroxypiperidine-4-carboxylic acid obtained in the above step (a) was dissolved in a mixed solvent of 1 N aqueous sodium hydroxide (1.4 ml) and tetrahydrofuran (2 ml), and the solution was added with benzyl chloroformate (0.1 ml). The reaction mixture was stirred at room temperature for 2 hours and 30 minutes, and then acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain crude 1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid. This crude 1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2.C(O)(C(F)(F)F)=O>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.69 mmol) was suspended in DMA (10 ml) and N-methylethanolamine (56 μl, 0.69 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 20 minutes at ambient temperature, and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials, 100 mg, 0.28 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 110° C. for 1 hour, then at 125° C. for 14 hours. The mixture was cooled to ambient temperature, and acidified with TFA. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O. The appropriate fractions were evaporated to a volume such that all of the acetonitrile had been removed. The resulting aqueous solution was basified with concentrated aqueous ammonia, and extracted with DCM (4×20 ml). The combined extracts were filtered through a silicone-treated filter paper, and concentrated in vacuo to give 5-[2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine as a yellow solid (40 mg, 34%); NMR Spectrum (CDCl3, 400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.12 (t, 2H), 4.25 (t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.00 (d, 1H), 7.04 (dd, 1H), 7.39 (d, 1H), 7.55 (dd, 1H), 7.61 (dd, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.56 (s, 1H), 10.26 (s, 1H); Mass spectrum MH+ 416.0