Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3]1
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Solvent: CC(=O)O
Product: CC1CCCC(CCC(=O)O)C1
Temperature: 150 °C
Reaction time: 72 h
Yield: 94.6 %

Procedure:
5% Ru/Al2O3 (3 g, 5 wt %), (2E)-3-(3-methylphenyl)acrylic acid (60 g, 0.37 mol) and acetic acid (300 mL) were charged into a 500 mL autoclave vessel. The mixture was vigorously stirred under a hydrogen atmosphere (40 bar) at 150° C., for 3 days. The catalyst was filtered and the product was dissolved in ethyl acetate (500 mL), washed with water (500 mL) and brine (500 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to yield crude 3-(3-methylcyclohexyl)propanoic acid (60 g, 0.35 mol, 95% yield) as a colourless oil.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([OH:9])[CH2:2]2.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([C:39]6[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=6)[CH:37]=5)[N:32]=[CH:31][N:30]=4)=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH3-]C#N.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O.CO.C(Cl)(Cl)Cl>[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([C:39]6[CH:40]=[CH:41][C:42]([CH2:43][N:8]7[CH:5]8[CH2:6][CH2:7][CH:1]7[CH2:2][CH:3]([OH:9])[CH2:4]8)=[CH:45][CH:46]=6)[CH:37]=5)[N:32]=[CH:31][N:30]=4)=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)(=[O:17])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC1CC2CCC(C1)N2
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(ccn5S(=O)(=O)c5ccccc5)c4)c3c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(-c5ccc(CN6C7CCC6CC(O)C7)cc5)cc34)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of CHCl3 (1.5 mL) and MeOH (3 mL) in a round-bottom flask under N2 was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495 mmol). AcOH was added to adjust the pH to 5. To the amine solution was added 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 (100 mg, 0.198 mmol) and the resulting solution was stirred at room temperature for 3 hours. NaCNBH3 was added to the reaction mixture which was then allowed to stir overnight at room temperature under an atmosphere of N2. The solution was diluted with CH2Cl2 and poured into 1N NaOH (10 mL). The aqueous layer was separated and extracted with another 2×15 mL of CH2Cl2. The organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to provide a yellow viscous oil. The residue was purified by flash chromatography (silica gel, CH2Cl2-10% MeOH/CH2Cl2) to provide 45 mg of compound 23 as a white solid in 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M++1, 100).
Reaction SMILES: C([N:8]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:20]4[C:28]5[O:27][CH:26]([CH3:29])[CH2:25][C:24]=5[CH:23]=[C:22]([O:30][C:31]([F:34])([F:33])[F:32])[CH:21]=4)[CH2:17][O:16]3)[C@:9]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][CH:11]2[S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])C1C=CC=CC=1>[Pd].C(O)C>[CH3:29][CH:26]1[CH2:25][C:24]2[CH:23]=[C:22]([O:30][C:31]([F:34])([F:32])[F:33])[CH:21]=[C:20]([C@H:18]3[CH2:17][O:16][C@:15]4([CH2:14][CH2:13][C@H:12]5[NH:8][C@@:9]4([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:10][CH:11]5[S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)(=[O:36])=[O:37])[CH2:19]3)[C:28]=2[O:27]1
Reactant: CC1Cc2cc(OC(F)(F)F)cc([C@H]3CO[C@]4(CC[C@@H]5C(S(=O)(=O)c6ccccc6)C[C@]4(c4ccccc4)N5Cc4ccccc4)C3)c2O1
Agent: [Pd]
Solvent: CCO
Product: CC1Cc2cc(OC(F)(F)F)cc([C@H]3CO[C@]4(CC[C@H]5N[C@@]4(c4ccccc4)CC5S(=O)(=O)c4ccccc4)C3)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A mixture of (1R*,2R*,4S*,5R*)-8-benzyl-2′,3′,4′,5′-tetrahydro-4′-[(2RS)-2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran-7-yl]-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Example 7; 200 mg, 0.29 mmol), 10% palladium on charcoal (375 mg, 0.35 mmol) and ethanol (25 ml) was stirred under hydrogen atmosphere (1 atm) at +70° C. for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (160 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N-:11]Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O.O.[Na+].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(#N)C.C(OCC)(=O)C>[CH3:17][S:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[N:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CSc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N=S(C)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
10.0 g (35.3 mmol) of chloramine-T trihydrate (Aldrich) are added to 5.0 g (29.6 mmol) of 1-methylsulphanyl-4-nitrobenzene in 120 ml of acetonitrile at room temperature. The mixture is stirred at room temperature for 4 hours and then diluted with ethyl acetate. The mixture is filtered with suction and the filter cake is washed with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is recrystallized from methanol. 2.2 g (6.5 mmol; yield: 22%) of the product are obtained.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:27]>>[CH:29]1([O:28][C:26]([N:11]2[CH2:12][C@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]2[C:8](=[O:9])[NH:7][C:4]2([C:2]#[N:3])[CH2:6][CH2:5]2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)OC2CCCC2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with cyclopentyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid cyclopentyl ester as a colorless oil. MS: 466.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH:10]=[N:9][C:8]=12)(O)=[O:2].[NH2:28][C:29]1([C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:7]3[N:6]=[CH:5][C:4]([C:1](=[O:2])[NH:28][C:29]4([C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]4)=[C:8]3[N:9]=[CH:10][C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)C1(N)CCS(=O)(=O)CC1
Reactant: O=C(O)c1cnn2c(-c3ccc(Cl)cc3F)c(-c3ccccc3Cl)cnc12
Product: COC(=O)C1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4F)c(-c4ccccc4Cl)cnc23)CCS(=O)(=O)CC1
Yield: 79 %

Procedure:
The compound obtained in Reference Example All (3-carboxy-7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine; 39 mg) and methyl 4-amino-1,1-dioxotetrahydrothiopyran-4-carboxylate (20 mg) were treated in the same manner as described in Example A1 to give 7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)-3-[N-(4-methoxycarbonyl-1,1-dioxotetrahydrothiopyran-4-yl)-carbamoyl]pyrazolo[1,5-a]pyrimidine (45 mg, yield: 79%) as a pale yellow powder.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
(5R)-5-(Azidomethyl)-3-(4-Iodophenyl)-1,3-oxazolidin-2-one (8.0 g, 23.2 mmol) was dissolved in acetonitrile (160 ml) and water (16 ml). Triphenylphosphine (7.3 g, 27.9 mmol) was added and the mixture stirred at room temperature overnight. The volatiles were removed by concentration in vacuo, and the resulting residue partitioned between water (200 ml) and dichloromethane (200 ml). The aqueous layer was extracted with dichloromethane (2×200 ml) and dried over sodium sulfate. The crude material was purified by flash chromatography on silica gel with 0-10% methanol in dichloromethane as the eluent giving the desired product (6.0 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)=[C:14]([NH2:15])[C:9]2=[C:8]([CH3:22])[C:7]=1[Cl:23].C[Si](C)(C)[O-].[K+]>C1COCC1>[NH2:15][C:14]1[C:9]2[C:10](=[N:11][C:6]([O:5][CH2:4][C:3]([OH:24])=[O:2])=[C:7]([Cl:23])[C:8]=2[CH3:22])[S:12][C:13]=1[C:16](=[O:21])[NH:17][CH:18]1[CH2:20][CH2:19]1
Reactant: COC(=O)COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid methyl ester (0.940 g, 2.54 mmol) in THF (20 ml) is added 95% potassium trimethylsilanolate (1.63 g, 12.71 mmol). The resulting mixture is stirred at room temperature for 2 hours and then quenched by the addition of water (50 ml). The mixture is acidified to pH2 by the addition of 1 N HCl, and then extracted with EtOAc (100 ml). The organic layer is washed with brine (40 ml), then dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow solid (0.693 g, 77%). Mass (m/z): 355.9 (M++1), 354.0 (M+−1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([CH2:7][C:6]1[CH:19]=[CH:20][CH:21]=[C:4]([Cl:3])[CH:5]=1)[C:14]([OH:16])=[O:15])[CH3:13]
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of potassium hydroxide (26 g) in absolute ethanol (375 ml) is added during 30 minutes to an ice-cold solution of diethyl 3-chlorobenzylmalonate (112 g) in absolute ethanol (375 ml). The solution is stirred at room temperature for 18 hours, and the solvent removed under reduced pressure. The residue is dissolved in water (1200 ml) and the solution cooled in an ice-bath. Concentrated hydrochloric acid (29 ml) is added, and the solution extracted with ether (2×350 ml). The combined ether solutions are washed with water (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give as an oil, 3-chlorobenzylmalonic acid monoethyl ester; NMR (CDCl3) δ: 10.13 (s, 1H), 7.2 (m, 4H), 4.15 (q, 2H), 3.5 (m, 3H), 1.21 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Reactant: FC(F)(F)c1nnc(Br)s1
Product: Cc1c2n(c3c(-c4nnc(C(F)(F)F)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (10 mg, 14%), MS (ISP) m/z=371.5 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole (69.9 mg, 0.3 mmol).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.0 g, 3.78 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (2.08 ml of a 2M solution in tetrahydrofuran, 4.16 mmol). After stirring for 5 min tributyltin chloride (1.2 ml, 4.42 mmol) was added and the reaction stirred for 10 min at −78° C. then allowed to warm to ambient temperature to give a solution of 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine in tetrahydrofuran (ca. 0.15M): m/z (ES+) 474, 476, 478 (M++H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[F:8][C:7]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=[C:3]([F:12])[C:2]=1[C:23]1[N:19]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[N:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(F)c(-c2ccnn2C2CCCCO2)c1F
Reaction time: 0.17 h

Procedure:
To a solution of tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.04 mmol) in dimethoxyethane (30 mL), 2-bromo-1,3-difluoro-4-nitrobenzene (2.38 g, 10 mmol) in dimethoxyethane (20 mL) was added and the mixture was insufflated with nitrogen for 10 min. To the solution, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 15 mmol) in dimethoxyethane (30 mL) was added and the mixture was insufflated with nitrogen for 2 min, then 2 M sodium carbonate solution (40 mL) was added and the mixture was refluxed for 4 h. The mixture was cooled and the organic phase was concentrated to oil. By addition of diethyl ether a precipitate was obtained, filtered off and discarded. The filtrate was concentrated and purified by flash chromatography (eluant: dichloromethane/ethyl acetate 20:1). The title compound was obtained as oil (1.27 g, 40%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:25])=[N:2]1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:25][C:39]([C:35]2[S:36][CH:37]=[CH:38][C:34]=2[CH3:33])=[O:40])=[N:2]1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CN1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCN(C)CC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a similar manner to Example 2, crude 3-{2-[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (262 mg, 0.72 mmol) obtained in Step 1 was dissolved in ethanol (10 mL) and was reacted with tin (0.26 g, 2.2 mmol) and concentrated hydrochloric acid (1.3 mL) at room temperature to obtain 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazine-1-yl)phenylamine. In a similar manner to Example 29, 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazin-1-yl)phenylamine (0.10 g, 0.30 mmol) was dissolved in THF (5.0 mL) and the solution was added with triethylamine (0.13 ml, 0.90 mmol) and 3-methylthiophenecarbonyl chloride (0.05 g, 0.31 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained crude product was triturated in ethyl acetate to obtain Compound 228 (0.10 g, 73%).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:10]3=[C:9]([C:23]([O:25]C)=[O:24])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].C(O)C>C1COCC1>[C:19]([O:18][C:16]([N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]([C:23]([OH:25])=[O:24])=[C:10]2[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 7-tert-butyl 1-methyl 3-phenyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (3A) (1.6 g, 4.47 mmol) in THF (50 mL) was added aqueous LiOH (0.7 g in 18.5 mL water) and ethanol (13 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified to pH 4 with 1N aqueous HCl solution. The aqueous suspension was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give Intermediate 3B as a white solid in quantitative yield. The material was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.81 (m, 2H), 4.14 (m, 2H), 5.02 (s, 2H), 7.46-7.51 (m, 3H), 7.62-7.68 (m, 2H). LCMS (+ESI) m/z 344.23 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].C(Cl)(=O)[C:10](Cl)=[O:11]>ClCCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:10]=[O:11])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccco1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccco1

Procedure:
A suspension of 2-furoamide in 1,2-dichloroethane was treated with oxalyl chloride; 2-furoylisocyanate was isolated by distillation. This product was reacted with the hydroxypropylimidazole, as for the starting material of Example 12, to give 2-fluoro-4-[3-(fur-2-yl)carbamoyloxypropyl]-1-triphenylmethylimidazole, having the following n.m.r. spectrum in d6DMSO: 1.82 (m, 2H); 2.47 (t, 2H); 4.07 (t, 2H); 6.3 (s, 1H); 6.64 (m, 1H); 7.0-7.45 (m, 15H); 7.5 (m, 1H); 7.91 (m, 1H); 10.1 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[CH:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]2[C:21]([O:23]C(=O)[C:14]=2[CH:13]=1)=[O:22].C([O-])(=O)C.[Na+]>CN(C)C=O.O.C(OC(=O)C)(=O)C.I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:14]2[CH:13]=[CH:12][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: I
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(CCc2ccc(Br)cc2)c(C(=O)O)c1

Procedure:
A mixture of 103.2 g. of p-bromophenylacetic acid, 77.4 g. of benzene-1,2,4-tricarboxylic anhydride and 1.5 g. of sodium acetate was heated to 275° for 2 hours. The residue was dissolved in 1600 ml of hot dimethylformamide and the solution diluted with 400 ml of water, then cooled. The solution was then filtered to afford a mixture of 3-(p-bromobenzylidene)phthalide-5- and -6-carboxylic acids. 80 g. of this mixture was refluxed for 72 hours in 160 ml of acetic anhydride and 240 ml of 57% aqueous hydriodic acid containing 35.2 g. of red phosphorus. The mixture was cooled in ice and diluted with 1000 water. The solution was filtered and the residue dissolved in 800 ml dimethylformamide and filtered. The filtrate was evaporated to yield a residue which upon recrystallization from benzene: ethanol (3:1) yielded 4-(p-bromophenethyl)benzene-1,3-dicarboxylic acid. The mother liquors were evaporated and the residue recrystallized from ethyl acetate to afford 2-(p-bromophenethyl)benzene-1,4-dicarboxylic acid. 8.5 G. of 2-(p-bromophenethyl)-benzene-1,4-dicarboxylic acid was stirred at 170° for 6 hours in a mixture of 40 ml of polyphosphonic acid and 30 ml of tetrahydrothiophene-1,1-dioxide. The mixture was then poured into water and the product filtered off and recrystallized from aqueous dimethylformamide to yield 2-carboxy-7-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene mp 252°-254°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][O:17][C:18]([C:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(CC)CC)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:52].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]([C:20]3[C:32]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:52]
Reactant: O=C(OCCBr)c1cccc2c1Cc1ccccc1-2
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCN1CCN(c2cccc(Cl)c2)CC1)c1cccc2c1Cc1ccccc1-2

Procedure:
To a stirred solution of 2-bromoethanol (3.3 g, 0.026 mol) in 50 mL of methylene chloride, fluorene-1-carboxylic acid chloride (6 g, 0.026 mol) and triethylamine (5 g, 0.05 mol) were added. The reaction mixture was stirred at room temperature overnight. The methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 7 g of the intermediate fluorene-1-carboxylic acid bromoethyl ester. The title compound was prepared by stirring 4-(3-chlorophenyl)piperazine (2.6 g, 0.011 mol), fluorene-1-carboxylic acid bromoethyl ester (3.5 g, 0.011 mol) and triethylamine (2.5 g, 0.025 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.68 in 30% methanol/ethylacetate system) was separated and converted to the dihydrochloride salt with ethanolic HCl (1.8 g, 31% yield), mp. 215°-217° C.