Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11](Cl)([CH3:13])=[O:12]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:12])[CH3:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of indan-5-amine (43 g, 0.31 mol) and TEA (51.3 mL, 0.370 mol) in 400 mL of anhydrous DCM was added a solution of AcCl (23.6 mL, 0.340 mol) in 100 mL of anhydrous DCM dropwise at 0° C. then and stirred for 0.5 h at RT. After the reaction was completed, 500 mL of DCM was added to the reaction mixture, and the mixture was washed with water, 10% HCl solution, 10% NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[C:22]([F:31])[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: Fc1cc(CBr)ccc1OC(F)(F)F
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 4-(bromomethyl)-2-fluoro-1-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.81 min.; [M+H]+: 428.21 g/mol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[N:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2nccc(CCl)n2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2nccc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)n2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl) pyrimidine (300 mg) and piperazine (44 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O>[N+:12]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Temperature: 40 °C

Procedure:
A solution of 3-trifluoromethylphenol (3.0 mL, 25 mmol) in HOAc (10 mL) is added dropwise to a solution of 65% nitric acid (2.0 mL, 278 mmol) in HOAc (10 mL) at 0° C. The mixture is warmed to 40° C. and when the reaction is complete it is cooled to RT and partitioned between water and EtOAc. The organic layer is concentrated and the residue is chromatographed using 10% EtOAc/hexane as eluent to afford the title compound as a yellow oil: (M−1)−=206.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([NH:52][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:36])[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 37.6 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (1.8 g, 3.1 mmol) was reacted with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester(Aldrich, 931 mg, 4.65 g, 4.65 mmol), HATU (2.12 g, 0.92 mmol) and iPr2NEt (2.7 mL, 15.5 mmol) in CH2Cl2 at room temperature overnight, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give a white solid (0.758 g, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2].[H-].[Na+].[C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:26](=[O:28])[CH3:27])[C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OCCCCBr
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(CCCCOC(C)=O)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Part A: 1-(4-Methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.0 g, 3.17 mmol) was dissolved in N,N-dimethylformamide (40 mL) and cooled to 0° C. Sodium hydride (60%, 0.317 g, 7.93 mmol) was added followed by 4-bromobutyl acetate (0.918 mL, 6.34 mmol). The reaction was stirred at rt overnight, quenched with 1N hydrochloric acid (200 mL), extracted with ethyl acetate (3×250 mL), washed with water (2×200 mL), washed with brine (1×200 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent to afford 6-(4-acetoxy-butyl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.490 g, 36%). The ester (0.490 g, 0.114 mmol) was dissolved in 5% NH3/ethylene glycol (6 mL) in a pressure tube, heated at 80° C. for 2 hr, cooled, quenched with water (100 mL), extracted with ethyl acetate (3×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate gradient and 0–100% methanol/ethyl acetate gradient as the eluents to afford 0.295 g (72%): 1H NMR (CHCl3) δ 7.45 (d, j=8.8 Hz, 2H), 6.97 (d, j=9.1 Hz, 2H), 6.83 (s, 3H), 5.49 (s, 3H), 3.84 (s, 3H), 3.66 (t, j=6.2 Hz, 2H), 3.51 (t, j=7.3 Hz, 2H), 3.23 (t, j=6.8 Hz, 2H), 1.72–1.55 (m, 4H) ppm; Mass Spec 357.3(M−H)−.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:22])[CH2:20]Br)=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+].ClCCl.C(O)(=S)C>CO>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:22])[CH2:20][S:25][C:23](=[O:26])[CH3:24])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reactant: CC([O-])=S
Agent: CC(O)=S
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)SCC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1

Procedure:
The mono-brominated sulfonamide from step 2 (0.194 g, 0.509 mmol) was was dissolved in methanol (2 ml) before potassium thioacetate (0.0639 g, 0.560 mmol) was added as a solid. LC-MS of the resulting yellow solution shows the reaction is complete in minutes. Evaporation of the volatiles leaves a tan residue which was taken up into dichloromethane (4 ml), during which the disulfide of the thioacetic acid was deposited and filtered. The desired thioester could then be recrystallized from dichloromethane/hexanes (0.080 g, 0.214 mmol, 42%). LC-MS (ES+): 376 [MH]+ m/e. 1H-NMR (DMSO): 7.87 (d, 3H), 7.78 (s, 1H), 7.7 (m, 1H), 7.57 (m, 3H), 4.41 (s, 2H), 3.99 (t, 2H), 3.06 (t, 2H), 2.34 (s, 3H)
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH2:13][CH2:14][C:15](OC)=[O:16])=O)=[CH:9][C:8]=1[OH:21])[CH:5]=[CH2:6]>C(O)(=O)C>[CH2:4]([C:7]1[CH:20]=[CH:19][C:10]([C:11]2[CH2:13][CH2:14][C:15](=[O:16])[NH:2][N:3]=2)=[CH:9][C:8]=1[OH:21])[CH:5]=[CH2:6]
Reactant: NN
Reactant: C=CCc1ccc(C(=O)CCC(=O)OC)cc1O
Solvent: O
Solvent: CC(=O)O
Product: C=CCc1ccc(C2=NNC(=O)CC2)cc1O
Yield: 94.4 %

Procedure:
Hydrazine hydrate (4.5 ml, 0.09 mole) was added to a stirred solution of methyl 3-(4-allyl-3-hydroxybenzoyl)propionate (5.6 g, 0.023 mole) in glacial acetic acid (60 ml) and the mixture heated under reflux for one hour. Evaporation under reduced pressure gave a residue which was triturated with water to give 6-(4-allyl-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (5 g, m.p. 175°-178°C, 96%). The pure pyridazinone, recrystallised from ethanol had m.p. 178°-180°C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4].[OH-].[Li+].Cl>C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:29])=[C:5]([C:3]([OH:4])=[O:2])[S:28][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-[4-Fluoro-2-(tetrahydro-pyran-4-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methylester (13.45 g) was dissolved in THF (100 ml) and lithium hydroxide (1M; 80.5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. The mixture was acidified with HCl (1M) to pH 2, the resultant precipitate was filtered and washed with water.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].C(N(CC)CC)C.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[Si:14]([O:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C=CCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccco1

Procedure:
To a freshly distilled solution of 2(5H)-furanone (2.86 g, 34 mmol) in dichloromethane (20 ml), distilled triethylamine (6.6 ml. 47.4 mmol) is added under argon at 0° C. and then rapidly followed by tert-butyldimehylsilyltrifluoromethane sulfonate (8.6 ml, 37.3 mmol) The reaction mixture is allowed to return to room temperature and the stirring is maintained for two hours. The solvent is then removed under reduced pressure and the oily residue is purified by flash chromatography on silica gel (ethyl acetate-heptane, 1:9) in order to thus obtain compound 10 (Z=O) in the form of a slightly colored oil (5.3 g, 79%). The spectroscopic data for this compound (1H and 13C NMR) are identical to those described in the literature (G. Rassu, Z. Zanardi, L. Battistini, E. Gaetani, G. Casiraghi, J. Med. Chem ., 1997, 40, 168).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35]C)=[O:34])[CH2:30]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:15]([F:27])[CH:14]=2)[O:10][N:9]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:15]([F:27])[CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1
Yield: 81.9 %

Procedure:
The title compound (0.11 g) was synthesized in a yield of 83% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-[(4-ethyl-5-{5-[3-fluoro-4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (0.14 g, 0.27 mmol) that was obtained in Example 20 (20c) and a 1 N aqueous solution of sodium hydroxide (0.81 mL, 0.81 mmol).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[I:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:18][C:16]1[CH:15]=[CH:14][C:13]([I:19])=[C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:20])[F:21])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOC(c1cc(C)ccc1I)(C(F)(F)F)C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOC(c1cc(CBr)ccc1I)(C(F)(F)F)C(F)(F)F
Temperature: 78 °C
Yield: 76.5 %

Procedure:
Compound 3 (2.51 g, 5.86 mmol), benzoyl peroxide (57 mg, 256 μmol) and N-bromosuccinimide (1.038 g, 8.79 mmol) were dissolved in 25 mL carbon tetrachloride. The solution was degassed, placed under nitrogen atmosphere and heated 15 h at 78° C. After cooling to room temperature, the mixture was filtered, and the solid washed with carbon tetrachloride. The filtrate was evaporated under reduced pressure to give a residue which was purified over silica gel using heptane/acetone as eluant to give 2.27 g (4.48 mmol, 76% yield) of a white solid.
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[C:7]([N:11]([C:16]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:19]3[C:20]([C:30]([O:32]CC)=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.CO.Cl>C1COCC1.O>[Br:4][C:5]1[CH:6]=[C:7]([N:11]([C:16]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:19]3[C:20]([C:30]([OH:32])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N(c1cccc(Br)c1)c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
Lithium hydroxide monohydrate (68.5 mg, 1.630 mmol) was added to a suspension of ethyl 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (311 mg, 0.543 mmol) in THF:MeOH:water/3:1:1 (10 mL). The mixture was stirred at room temperature overnight. The mixture was acidified with 2N aqueous HCl and the volatile solvents were evaporated. The residue was partitioned between EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate and concentrated to give 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylic acid (309 mg, quantitative) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01-8.13 (m, 2H) 7.77 (s, 1H) 7.66 (s, 1H) 7.54 (t, J=1.95 Hz, 1H) 7.39 (dd, J=8.21, 1.37 Hz, 1H) 7.30-7.36 (m, 1H) 7.17-7.26 (m, 3H) 3.27 (s, 3H) 2.11 (s, 1H) 0.74-1.18 (m, 3H) 0.48-0.74 (m, 1H). LCMS (m/z, ES+)=544, 546 (M+H, M+2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=3)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:8][CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(NC(=O)c2ccc(C)cc2)cc1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: Cc1ccc(C(=O)Nc2ccc(C#Cc3cncc(C(=O)N=[S@@](C)(=O)c4ccccc4)c3)cc2)cc1
Yield: 81 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-4-methyl-benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (118 mg, 81%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Product: COc1cc(C=Cc2cc(OC)c(C(C)C)c(OC)c2)cc(OC)c1
Yield: 25 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 3,5-dimethoxybenzaldehyde in 25% yield as the same procedure as described in example 5(b)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C(C1[C:25]2[C:20](=C[CH:22]=[CH:23][CH:24]=2)[C:19]([N:26]=[C:27]=[S:28])=CC=1)#N.Cl.NC1(CCl)CCCC1>>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:1]=[C:27]2[NH:26][CH2:19][C:20]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[S:28]2)=[CH:3][CH:4]=1)#[N:13]
Reactant: N#Cc1ccc(N)c2ccccc12
Reactant: N#Cc1ccc(N=C=S)c2ccccc12
Agent: Cl
Agent: NC1(CCl)CCCC1
Product: N#Cc1ccc(N=C2NCC3(CCCC3)S2)c2ccccc12

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. 1-Amino-4-cyanonaphthalene was converted into 4-cyano-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate to Method C1a to give 2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl.CO>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 69.7 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (4-aminophenyl)boronic acid (44 mg, 0.32 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.74 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble light pink mixture was irradiated (microwave) at 150° C. for 30 min. After cooling, DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated solid was treated with MeOH. The solids that precipitated were filtered and dried to afford the title compound (63 mg, 66%) as a yellow solid. LCMS E-S (M+H)=431.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1 H), 8.88 (t, J=4.93 Hz, 1 H), 8.27 (s, 1 H), 8.01 (s, 1 H), 7.99 (d, J=2.02 Hz, 2 H), 6.69 (s, 1 H), 6.67 (s, 1 H), 5.90 (s, 1 H), 5.61 (s, 2 H), 5.24-5.32 (m, 1 H), 4.40 (d, J=4.80 Hz, 2 H), 2.22 (s, 3 H), 2.13 (s, 3 H), 1.53 (s, 3 H), 1.51 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.ClCCl.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH4-].[Na+]>C(O)(=O)C>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Reactant: CN1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a stirred solution of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (150 mg, 0.4 mmol) in dryness dichloromethane (10 mL) was added acetic acid followed by 1-methylpiperazine (121 mg, 1.2 mmol). After the addition, the mixture was stirred at room temperature for 1 h, Then the mixture was cooled to 0° C. Sodium borohydride (130 mg, 0.2 mmol) was added. After the addition, the mixture was stirred at this temperature for 3 hr. Dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as white solid (22 mg, yield 12%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.31 (s, 3H), 2.36-2.48 (m, 8H), 3.37-3.48 (dd, 2H), 4.30 (dd, 1H), 4.71 (dd, 1H), 7.01 (s, 1H), 7.05 (dd, 1H), 7.17-7.23 (m, 5H), 7.25-7.28 (m, 2H), 7.56 (dd, 1H), 7.61-7.65 (t, 1H); LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH3:21])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1.[C:23](#N)C>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1
Reactant: CC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: CC#N
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
This residual partially resolved [(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (2.86 gm., 0.0118 mole) is treated with 1(-)cinchonidine (3.47 gm., 0.0118 mole) and the mixture dissolved in the minimum quantity of acetonitrile. After cooling for 48 hours, the salt that separates is removed by filtration and recrystallized twice from the minimum volume of acetonitrile. The pure salt is suspended in water (50 ml), treated with 6 normal hydrochloric acid (5 ml) and the precipitate that separates is removed by filtration and dried. This solid is recrystallized from a miture of tetrahydrofuran and ethyl ether to give the (-) enantiomer of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid, m.p. 239°-241° C.,