Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cl
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
To a suspension of 50 ml of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.90 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. The resulting mixture became homogeneous after 5 minutes. Thereto was added 2.45 g (10.0 mmol) of N-(bromoethyl)phthalimide and the mixture was refluxed for 29 hours. This was cooled to room temperature, then poured into 200 ml of a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated and was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 1.37 g of N-(2-chloroethyl)-phthalimide and further development with chloroform resulted in 0.964 g (yield: 41%) of white cyrstals of N-[2-(N-methoxy-N-methylamino)ethyl]phthalimide.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[NH:26][C:25](=[O:36])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[C:29]([NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN(C)C)CCC3)C(=O)N2
Yield: 76.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 39 (75 mg, yield 76.5%) as a brown solid.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][C@H:3]([C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8])[NH:2]2.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:2]2[C@@H:3]([C:7]([NH:9][C@H:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[CH3:11])=[O:8])[CH2:4][CH:5]3[CH:1]2[CH2:6]3)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compounds (D149) (14 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((3R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (D106) (11 mg) and 4-(trifluoromethyl)-benzylbromide (0.007 ml). (Na2CO3: 3 eq; Reaction time: 18 hrs; 68° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCO>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccccc2)NC#N)c1
Temperature: 60 °C

Procedure:
[2′-(3-Cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.10 g, 0.17 mmol) and benzylamine (0.04 mL, 0.34 mmol) were combined in EtOH (1 mL) and heated to 60° C. The reaction was monitored by analytical LCMS, and additional benzylamine (0.04 mL, 0.34 mmol) was added to push the reaction to completion. Further benzylamine (0.10 mL, 0.92 mmol) was added, and the reaction was heated for a total of 48 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:13][CH:12]3[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:6]=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=1)[N:21]=[CH:22]2.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32]([C:2]3[CH:3]=[N:4][N:5]([CH:7]4[CH2:13][CH:12]5[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]5)[CH2:8]4)[CH:6]=3)[CH:33]=1)[N:21]=[CH:22]2
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
Reactant: CN1C2CCC1CC(n1cc(I)cn1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn1)C2
Temperature: 100 °C

Procedure:
A solution of 3-(4-iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane (42.7 mg, 0.135 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (0.070 g, 0.18 mmol), potassium carbonate (55.9 mg, 0.404 mmol), and Pd(PPh3)4 (9 mg, 0.008 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 10% MeOH in CHCl3], passing through an SCX cartridge, and finally by the MDP. The fractions containing product were combined, concentrated in vacuo, and partitioned between CHCl3 and sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=1.64-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.97-2.06 (m, 2H), 2.07-2.17 (m, 2H), 2.26 (s, 3H), 3.20 (br. s., 2H), 4.47 (tt, J=11.7, 5.9 Hz, 1H), 6.89 (br. s., 2H), 7.54 (dd, J=9.9, 8.4 Hz, 1H), 7.87 (s, 1H), 8.03 (dd, J=8.4, 4.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.37 (s, 1H), 9.64 (s, 1H). MS (ES+): m/z=463.13/465.15 (76/24) [MH+]. HPLC: tR=1.88 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)N1CCOCC1
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>CC(C)=O>[O:16]=[C:5]1[C:4]2[CH:3]=[C:2]([O:1][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(CCCl)Oc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 25 °C

Procedure:
5 g (22 mmol) of 2-hydroxy-9H-thioxanthen-9-one was dissolved in 200 ml refluxing acetone. 3.6 ml (3.5 g, 44 mmol) pyridine was added, followed by the addition of 5.6 g (44 mmol) 3-chloropropionyl chloride. The mixture was refluxed for 5 hours. The solvent was removed under reduced pressure, after cooling down to room temperature and the residue was dissolved in 200 ml methylene chloride. The methylene chloride was extracted with 150 ml of a 1 M Na2CO3 solution and 150 ml of a 0.1 N hydrochloric acid solution. The organic fraction was dried over MgSO4 and evaporated under reduced pressure. 3-chloro-propionic acid 9-oxo-9H-thioxanthen-2-yl ester was isolated by preparative column chromatography on a SVP D40 Merck NP column, using a gradient elution from methylene chloride (20 minutes isocratic elution) to methylene chloride/ethyl acetate 80/20 over 30 minutes and a flow rate of 50 ml/min. 0.414 g of 3-chloro-propionic acid 9-oxo-9H-thioxanthen-2-yl ester (6%) was isolated as a white crystalline compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)c1ccc(F)cc1
Agent: Cn1cncc1C(O)c1ccccn1
Product: Cn1cncc1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 33: step b using (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (Intermediate 89: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]2=[O:19])=[O:4].[H-].[Na+].[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]2=[O:19])=[O:4]
Reactant: CCOC(=O)C1Cc2ccc(C(=O)OC)cc2C1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)OCC)Cc2ccc(C(=O)OC)cc2C1=O
Temperature: 60 °C
Yield: 80.1 %

Procedure:
To a stirred solution of 3-oxo-indan-2,5-dicarboxylic acid 2-ethyl ester-5-methyl ester (Step 1, 500 mg, 1.9 mmol) in dry DMF (0.7 ml) was added sodium hydride (84 mg, 2.0 mmol, 60% in mineral oil) and then heated at 60° C. for 1 h. Then ethyl bromo acetate (350 mg, 2.0 mmol) was dissolved in dry DMF (1.4 ml) and added to the reaction mixture at room temperature and then again heated at 60° C. for 3 h. After completion of the reaction mixture was concentrated and H2O (5 ml) was added. The suspension was extracted with ethyl acetate and combined organic layer was washed with brine, dried and concentrated. The crude was purified by column chromatography using 20% ethyl acetate-hexane to give the desired compound (530 mg). 1H NMR (400 MHz, CDCl3) d 8.42 (1H, s), 8.30 (1H, d), 7.57 (1H, d), 4.37 (4H, m), 3.92 (3H, s), 3.90 (1H, d), 3.28 (2H, m), 2.90 (1H, d), 1.15 (3H, m) ppm.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:31]=[C:32]([C:36]2([OH:44])[CH2:42][CH:41]3[NH:43][CH:38]([CH2:39][CH2:40]3)[CH2:37]2)[CH:33]=[CH:34][CH:35]=1>CS(C)=O>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:43]4[CH:41]5[CH2:40][CH2:39][CH:38]4[CH2:37][C:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:45])[F:46])[CH:31]=4)([OH:44])[CH2:42]5)[O:27][C:17]3=2)[N:22]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CC2CCC(C1)N2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1C2CCC1CC(O)(c1cccc(C(F)(F)F)c1)C2)O3
Temperature: 100 °C
Yield: 34.4 %

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.70 g, 1.8 mmole) and 3-(3-trifluoromethyl-phenyl)-8-azabicyclo[3.2.1]octan-3-ol (0.59 g, 2.4 mmole) were combined in 3 mL of DMSO and heated at 100° C. under nitrogen for 4 hours. After cooling to room temperature, the mixture was partitioned between 400 mL of ethyl acetate and 400 mL of saturated sodium bicarbonate solution. The organic phase was removed, washed with 400 mL of water, dried over magnesium sulfate, filtered and concentrated in vacuum to 1.29 g of a crude oil. The residue was column chromatographed on silica gel using 10% methanol in ethyl acetate as eluant to give 0.30 g of a yellow oil. Crystallization from ethanol/ether with the addition of 0.073 g of fumaric acid gave 0 040 g of the (S)-enantiomer of the title compound as a light yellow solid, m.p. 146-150° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][CH:24]=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][C:24]([Cl:1])=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: CC(C)c1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of N-chlorosuccinimide (87.3 mg; 0.628 mmol) in chloroform (1 ml) was added a solution of 3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (229 mg; 0.523 mmol) in chloroform (2 ml) and the resulting solution was heated to 70° C. for 5 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (20 ml) and washed with water (3×10 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC gave the pure product 1-chloro-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (97 mg; 39%). LC-MS: tR=1.04 min.; [M+H]+=472.51 g/mol.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[CH:30]=[CH:29][C:13]([CH2:14][S:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CCOC(OC(OCC)=O)=O.[OH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C>[CH3:26][N:25]1[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:28])[N:17]=[C:16]1[S:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1]([N:48]3[CH2:49][CH2:50][CH:45]([OH:44])[CH2:46][CH2:47]3)=[O:3])=[CH:32][CH:31]=2)=[CH:30][CH:29]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)O)cc4)cc3)n(C)c(=O)c12
Reactant: OC1CCNCC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)N5CCC(O)CC5)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (1.00 g, 2.26 mmol) in DMF (10.0 ml) was added DEPC (0.755 g, 4.63 mmol) and the mixture was stirred at room temperature for 10 minutes. Then, 4-hydroxypiperidine (0.522 g, 5.16 mmol) was added and the mixture was stirred at room temperature for 4 hours. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and then concentrated under reduced pressure, and the residue was recrystallized from THF to provide colorless needles.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH3:17])[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1.[Cl:27][C:28]1[N:33]=[C:32](Cl)[CH:31]=[CH:30][N:29]=1.O>C(COC)OC>[Cl:27][C:28]1[N:33]=[C:32]([C:12]2[C:13]([CH3:17])=[C:14]([C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH:15]=[O:16])[CH:31]=[CH:30][N:29]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1C=O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccnc(Cl)n2)c(C)c1C=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
A 2 M aqueous solution of sodium carbonate (2.72 mL, 5.43 mol) and tetrakistriphenylphosphine palladium(0) (209 mg, 0.181 mmol) were added to a suspension of the 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde obtained in Example 4-1 (500 mg, 1.81 mmol) and 2,4-dichloropyrimidine (405 mg, 2.72 mmol) in dimethoxyethane (5.4 mL) at room temperature. The mixture thus obtained was stirred at 80° C. for 10 hours. Thereafter, the resulting solution was cooled to room temperature. Water was added to the reaction solution, and the precipitated crude product was collected by filtration and was then washed with water and diisopropyl ether to obtain the title compound (418 mg, yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.S(Cl)([Cl:16])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:16])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(CCl)n1
Reaction time: 0.67 h

Procedure:
To a solution of methyl 4-chloro-6-(hydroxymethyl)-2-pyridinecarboxylate (166 mg, Ref: Kittika et al., Tetrahedron, 44 (10), 2821, (1988)) in dry dichloromethane (3 ml) was added thionyl chloride (66 μl). The solution was stirred for 40 minutes. LC/MS indication reaction completion. Solvent was removed u.r.p. (under reduced pressure) to give a white solid. Toluene (˜2 ml) added then removed u.r.p. The residue was dried in vacuo to give a white solid. (175 mg, 97%). LC/MS [MH+]=220/222, Rt=2.51 min. Title compound obtained as the free base.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([NH:17][CH2:18][CH3:19])=[C:15]([C:20]([OH:22])=[O:21])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.O.[C:31](OC(=O)C)(=[O:33])[CH3:32]>S(=O)(=O)(O)O>[C:31]([CH2:19][CH2:18][NH:17][C:16]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:6][CH:5]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:20]([OH:22])=[O:21])=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)(=[O:33])[CH3:32]
Reactant: CCNc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)CCNc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 2.8 g portion of 2-[1,1'-biphenyl]-4-yl-3-(ethylamino)-6-fluoro-4-quinolinecarboxylic acid was suspended in 25 ml of acetic anhydride. To this suspension was added 5 drops of concentrated sulfuric acid, then the mixture was heated at 80° C. for 2 hours. The solution was cooled, added to 200 ml of water and stirred for 30 minutes. The resulting solid was collected, washed with water, then dichloromethane and dried at 110° C. in vacuo, giving 2.0 g of the desired product as a pale yellow solid, mp 260°-262° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[C:6]([CH:15]=[C:16]([N+:18]([O-])=O)[CH3:17])[C:5]=2[CH:4]=1.[C:21]([CH:24]([CH:26]([C:28]([O-:30])=[O:29])O)O)([O-:23])=[O:22].[Na+].[K+].C(O)(=O)/C=C/C(O)=O>CC(O)C>[C:28]([OH:30])(=[O:29])/[CH:26]=[CH:24]/[C:21]([OH:23])=[O:22].[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[C:6]([CH2:15][CH:16]([NH2:18])[CH3:17])[C:5]=2[CH:4]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: COc1ccc2c(c1)c(C=C(C)[N+](=O)[O-])c1n2CCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc2c(c1)c(CC(C)N)c1n2CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
(RS)-1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine fumarate was prepared from 1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene according to hthe method described in Example 1 with the following modifications: the reaction mixture was heated under reflux for 4 h, cooled to 0° C. and aqueous potassium sodium tartrate solution (50 mL) was added slowly. The mixture was stirred for 30 min, filtered through a pad of kieselguhr and the filtrate was extracted with dichloromethane (3×30 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and concentrated in vacuo. The concentrate was dissolved in 2-propanol (1 mL) and added to a solution of fumaric acid (0.17 g, 1.5 mmol) in 2-propanol (20 mL) at 50° C. The solution was cooled to 0° C. and filtered. The filter-cake was washed (2-propanol, ether) and dried to give the title compound as a white solid (0.22 g, 42%): mp 194-196° C.; Found: C, 63.27; H, 6.80; N, 7.69%. C19H24N2O5 requires: C, 63.32; H, 6.71; N, 7.77%.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>C(O)(=O)C>[F:1][S:2]([F:10])([F:11])([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cccc(S(F)(F)(F)(F)F)c1

Procedure:
15 g (68.44 mmol) of 3-pentafluorosulfanylphenylamine was suspended with 10.14 g (68.44 mmol) of phthalic anhydride in 40 ml of a acetic acid and boiled under reflux for 2 h. The cool reaction mixture was admixed with 400 ml of water, heated in an ultrasound bath for 30 min and filtered. The residue was washed with water and subsequently with a little ethanol and dried under reduced pressure. 2-(3-Pentafluorosulfanylphenyl)isoindole-1,3-dione was obtained with a melting point of 188-190° C.