Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2.[CH3:28][NH:29][C@@H:30]([CH3:33])[CH2:31][OH:32]>>[CH3:28][NH:29][C@@H:30]([CH3:33])[CH2:31][O:32][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: CN[C@@H](C)CO
Product: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 71 %

Procedure:
The procedure described in Example 103, preparation of starting materials, was repeated using 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) and (2S)-2-(methylamino)propan-1-ol (obtained as described in Chacchio et al., Tetrahedron, 1995, 51, 5689) to give 5-{[(2S)-2-(methylamino)propyl]oxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 71% yield; NMR Spectrum: (CDCl3) 1.30 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.89 (m, 2H), 7.14-7.07 (m, 2H), 7.45 (d, 1H), 7.63 (m, 2H), 8.26 (s, 1H), 8.63 (s, 1H); Mass spectrum: MH+ 430.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13]C)=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[K+]>CO>[CH3:19][O:18][C:16]([C:8]1[CH:9]=[C:10]([CH:15]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:7]=1)[C:11]([OH:13])=[O:12])=[O:17]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)cc(-n2cccc2)c1
Temperature: 68 °C
Reaction time: 62 h
Yield: 71 %

Procedure:
A mixture of dimethyl 5-(pyrrol-1-yl)isophthalate (80.0 g) and potassium hydroxide (20.2 g) in methanol (3.1 l) was stirred for 62 hours at 68° C. After being cooled to room temperature, the solvent was evaporated in vacuo. The residue was dissolved in water and the solution was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (25.5 ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with diethyl ether to afford 3-methoxycarbonyl-5-(pyrrol-1-yl)benzoic acid (53.7 g).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=[O:26])[CH2:17]P(OCC)(OCC)=O)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2].[H-].[Na+].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH:34]=O>O1CCCC1>[C:1]([NH:4][CH:5]([C:16](=[O:26])[CH:17]=[CH:34][C:33]1[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=[C:31]([C:30]([F:29])([F:43])[F:44])[CH:32]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOP(=O)(CC(=O)C(Cc1csc2ccccc12)NC(C)=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1csc2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of the product of step (a) (10.6 g) in dry tetrahydrofuran (200 ml) was cooled to 0° C., treated with 60% sodium hydride in oil (1.07 g) and stirred for 1 hour. 3,5-Bistrifluoromethyl benzaldehyde (6.5 g) in dry tetrahydrofuran (50 ml) was added dropwise to the reaction mixture which was stirred for 1 hour before quenching with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (100 ml), dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica using ethyl acetate/petroleum ether (bp 60-80) (2:3) to yield the title compound as a pale yellow solid (10.3 g), mp=172°-173° C.; found: C, 56.15; H, 3:54; N, 2.79; C23H17F6NO2S.0.25H2O requires C, 56.38; H, 3.60; N, 2.86%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2C=CC=[C:12]([C:14]3(C[SeH])CC[CH2:17][O:16][C:15]3=[O:20])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH:13]1[CH2:17][O:16][C:15](=[O:20])[CH2:14][CH2:12]1
Reactant: O=C1OCCCC1(C[SeH])c1cccc(-c2cccc(Br)c2)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C1CCC(Cc2cccc(Br)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
5-(3-Bromophenyl)phenylselenylmethyl-tetrahydropyran-2-one (6.7 g, 15.8 mmole) is suspended in 100 ml dry toluene in an oven dried 250 ml 3-neck round bottom flask under nitrogen. The suspension is brought to solution by warming to 65° C. The solution is treated with tributyltin hydride (4.7 ml, 17.4 mmole), stirred for 10 minutes, and treated with azo(bis)isobutyrlnitrile (0.285 g, 1.74 mmole) in one lot. The reaction mixture is stirred 1.5 hours at 65° C., cooled to room temperature, and concentrated in vacuo to a pale oil. The oil is chromatographed over 250 g silica gel (230-400 mesh), eluting with 20% ethyl acetate/hexane and after a 2500 ml forerun collecting 60 ml fractions. Fractions 10-48 are combined and concentrated to afford 3.45 g of the title compound as a pale oil. Following the above procedures gives the title compound having the physical characteristic described below:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2.[N+:17]([O-])([OH:19])=[O:18].C(OCC)C>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2
Reactant: COC(=O)C1CCc2c(cccc2OC)C1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C1CCc2c(OC)ccc([N+](=O)[O-])c2C1
Temperature: 0 °C
Yield: 20 %

Procedure:
Methyl 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.1 g, 5 mmol; described in: Johnson, D. W.; Mander, L. N. Aust. J. Chem. 1974, 8, 1277-1286) dissolved in acetic anhydride (20 mL), was treated with 70% nitric acid (0.4 mL) at 0° C. for 1 h and the mixture was poured into ice-water and diethyl ether. The organic phase was separated, evaporated in vacuo and the residue triturated with diisopropyl ether to yield 0.27 g (20%) of the title compound as crystals: mp 100-104° C.; EIMS (70 eV) m/z (relative intensity) 265 (35, M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:8]=[C:7]([Cl:25])[N:6]=1)=[O:4]>C(O)C.Cl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:8]=[C:7]([Cl:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)c1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (3.46 g, 9.34 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 271.1 [M+H]+.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(=O)([O-])[O-].[Na+].[Na+]>[C:13]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CNCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C1CN(C(C)=O)CCC1=O
Temperature: 0 °C

Procedure:
To a vigorously stirred, ice-water cooled suspension of 2.0 g of 3-carbethoxy-4-piperidone in 20 ml of aqueous sodium carbonate is added 1 ml of acetic anhydride. The mixture is stirred in the cold for 30 minutes then extracted with ether. The organic layer is dried and evaporated to afford 1.5 g of colorless solid, m.p. 53°-55° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:24]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]([C:32](O)=[O:33])=[N:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:32]([C:26]3[NH:25][N:24]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=3)=[O:33])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of Intermediate 8-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCl (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmol) in DMF (3 mL) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.07 Hz, 3H), 2.54-2.67 (m, 2H), 2.84-2.97 (m, 2H), 4.02 (q, J=7.07 Hz, 2H), 4.54 (m, 1H), 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.39 (m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (s, 1H), 8.41 (s, broad, 1H).
Reaction SMILES: Cl.[C:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33](O)=[O:34])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C1COCC1.CN(C=O)C>[C:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([NH:45][OH:46])=[O:34])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(C(=O)c4ccccc4)CC3)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(C(=O)c4ccccc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (200 mg, 0.398 mmol), HOBT (107.4 mg, 0.796 mmol), EDC (152 mg, 0.796 mmol), TEA (0.111 ml, 0.796 mmol) and NH2OTHP (56 mg, 0.477 mmol) in THF (5 ml) and DMF (5 ml) was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH 98:2) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 2 h. The precipitate was filtered giving 115 mg of (E)-3-(4-{(E)-3-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy acrylamide as its hydrochloride salt.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: Cc1ccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)cc1

Procedure:
Example 8 was prepared according to Example 2 except that in Step A 1-(p-tolyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 143°-145° C.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[OH:41][CH2:42][CH2:43][CH2:44]C1C=CC(B(O)O)=CC=1>>[OH:41][CH2:42][CH2:43][CH2:44][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:16])=[O:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCc1ccc(B(O)O)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 64, using 4-(3-hydroxypropyl)phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C33H32N3O5S+ 582.2. Found m/z=582.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([OH:34])([CH2:32][CH3:33])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19](OC)=[O:20])\[CH2:8][CH3:9])[CH3:2].[BH4-].[Li+]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:18]=1[CH2:19][OH:20])[CH2:14][O:13][C:12]1[CH:11]=[C:10](/[C:7](/[CH2:8][CH3:9])=[CH:6]/[CH:5]=[CH:4]/[C:3]([CH2:32][CH3:33])([OH:34])[CH2:1][CH3:2])[CH:31]=[CH:30][CH:29]=1
Reactant: CC/C(=C\C=C\C(O)(CC)CC)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CC/C(=C\C=C\C(O)(CC)CC)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 122 mg (0.26 mmol) of dimethyl 4-[3-((1E,3E)-5-ethyl-5-hydroxy-1-ethylhepta-1,3-dienyl)phenoxymethyl]phthalate (prepared in a manner similar to Examples 65(a-c)) with 17 mg (0.78 mmol) of lithium borohydride, a colourless oil is obtained (m=91 mg; Y=85%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]1[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@@H:22]2[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN1C[C@@H](N)CCC1=O
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1C[C@@H](Nc2nc(Cl)nc3c2SCC3)CCC1=O
Temperature: 130 °C

Procedure:
0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130° C. until there is no further reaction, cooled and then evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method B). 0.26 g (III-5) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.06 min.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([C:12]([O:14]CC)=[O:13])=[C:8]([CH3:11])[NH:9][CH:10]=1)([OH:3])=[O:2].[OH-].[K+]>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([C:12]([OH:14])=[O:13])=[C:8]([CH3:11])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1c(CCC(=O)O)c[nH]c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]cc(CCC(=O)O)c1C(=O)O
Yield: 64 %

Procedure:
4-(2-Carboxyethyl)-3-ethoxycarbonyl-2-methylpyrrole (Bulter, A. R., and George, S. D. (1993) Tetrahedron 49: 7017-7026) was hydrolyzed using potassium hydroxide (KOH) in ethanol (EtOH) to give 4-(2-carboxyethyl)-2-methyl-1H-pyrrole-3-carboxylic acid (64%).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].Br.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19]N2)[CH2:16][CH2:15]1.C=O>CO>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:2]2[CH3:1])[CH2:16][CH2:15]1
Reactant: COc1cc2c(cc1F)CCNC2C1(c2ccc(Cl)cc2Cl)CC1
Reactant: [BH3-]C#N
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1F)CCN(C)C2C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium cyanoborohydride (2.8 g) was added at 5° C. to a mixture of 1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (10 g, prepared as described in Example RC4), methanol (100 ml) and 37-40% aqueous formaldehyde solution (7.2 ml). The mixture was warmed to ambient temperature and stirred for 1.5 hours. The solvent was removed in vacuo and the residue partitioned between water and dichloromethane. The organic phase was washed with concentrated ammonia solution, then water, and dried over magnesium sulphate. The solvent was removed in vacuo to yield 1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline as a gum which solidified on standing.
Reaction SMILES: N(CCO)(CCO)CCO.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([CH3:27])[CH:26]=1>CS(C)=O>[N+:28]([C:24]1[CH:23]=[CH:22][C:21]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:26][C:25]=1[CH3:27])([O-:30])=[O:29]
Reactant: NCCCn1ccnc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: OCCN(CCO)CCO
Solvent: CS(C)=O
Product: Cc1cc(NCCCn2ccnc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 17 h

Procedure:
150 ml of dimethyl sulfoxide were introduced into a 500 ml three-necked flask and treated with 22.6 g of triethanolamine (99% strength), 28.7 g of 1-(3-amino-propyl)imidazole (98% strength) and 24.2 g of 5-fluoro-2-nitrotoluene (96% strength). The mixture was stirred at 80° C. for 17 h. Following this, the batch was cooled to room temperature and poured onto 1 l of ice, a yellow oil depositing, which crystallized thoroughly after about 1 h. The precipitate thus resulting was filtered off with suction, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH2:14][C:15]1[C:19]([F:20])=[C:18]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)[NH:17][CH:16]=1)[CH3:13].[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH2:14][C:15]1[C:19]([F:20])=[C:18]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)[N:17]([S:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:53])=[O:52])[CH:16]=1)[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(CN(C)Cc2c[nH]c(-c3cccnc3F)c2F)c(OC)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(C)Cc2cn(S(=O)(=O)c3ccccc3)c(-c3cccnc3F)c2F)c(OC)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 1-(2,4-dimethoxyphenyl)-N-{[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}-N-methylmethanamine (2.98 g) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 421 mg) under ice-cooling. After stirring at the same temperature for 30 min, 15-crown-5 (1.80 mL) was added dropwise. After further stirring for 15 min, benzenesulfonyl chloride (1.15 mL) was added dropwise. After stirring for 1 hr at the same temperature, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=9:1→7:3) to give the title compound as a yellow oil (yield 2.95 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:26]=[O:27])C>C1COCC1>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:26]=[O:27])=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3,5-Dichloro-phenyl)-propionic acid tert butyl ester (1 g, 3.6 mmol) in THF (50 mL) at −78 C was added dropwise s-butyl lithium (1.4 M cyclohexanes; 5.7 mL, 2.2 eq). The resulting red colored homogeneous solution was stirred under nitrogen at −78 C for one hour, at which time DMF (560 mL, 2 eq) was added. After 30 minutes, quenched reaction with saturated ammonium chloride solution at −78 C. Removed ice bath and allowed reaction to reach room temperature. Evaporation of volatiles in vacuo, partitioned between water and ethyl acetate. Combined ethyl acetate fractions were dried over magnesium sulfate and appropriately loaded onto a silica gel column. Isolated 600 mg of titled compound after chromatography (isocratic 20% ethyl acetate/n-heptanes). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.35-1.44 (m, 10H) 2.55 (t, J=7.45 Hz, 2H) 2.90 (t, J=7.45 Hz, 2H) 7.23 (s, 2H) 10.45 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To the product from Example 88A (4.2 g, 9.8 mmol) dissolved in dichloromethane (100 mL) was added pyridine (1.62 mL, 20 mmol) followed by the dropwise addition of 2,2,2-trichloroethyl chloroformate (2.29 g, 10.8 mmol). The resultant solution was stirred for 4 hours and then concentrated under vacuum. The mixture was then poured into water (200 mL), the pH of the solution adjusted to 5 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried to provide the title compound (6.0 g, 100%).