Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C@H:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1c1ccccc1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C[C@H]1c1ccccc1

Procedure:
Intermediate 1 was coupled with 2-phenyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 465.
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N+:15]([O-])=[C:14]([CH3:20])[C:13]=3[CH3:21])[CH2:6][O:5]2)[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:24])C.[OH-].[Na+]>CO>[CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:20][OH:24])[C:13]=3[CH3:21])[CH2:6][O:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC2(CCC2)OC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(CO)c(C)c1OCC1COC2(CCC2)OC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
The 4-(5,9-dioxaspiro[3.5]non-7-ylmethoxy)-2,3,5-trimethylpyridine 1-oxide (1.97 g, 6.72 mmol) obtained in the step (13b) was mixed with acetic anhydride (20 ml, 212 mmol). The mixture was stirred at 85° C. for 1.5 hours. After cooled to room temperature, the reaction mixture was concentrated. To the residue, methanol (20 ml) and a 5N aqueous sodium hydroxide solution (20 ml, 100 mmol) were added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with a 2N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (1.69 g, yield: 85.7%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.C(O)(=S)C.[C:20]([OH:24])(=[S:23])[CH2:21][CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH:9]([CH2:13][S:23][C:20](=[O:24])[CH2:21][CH3:22])[C:10]([OH:12])=[O:11])=[O:7])=[CH:14][CH:15]=1
Reactant: C=C(CC(=O)c1ccc(Br)cc1)C(=O)O
Reactant: CCC(O)=S
Agent: CC(O)=S
Product: CCC(=O)SCC(CC(=O)c1ccc(Br)cc1)C(=O)O
Yield: 71 %

Procedure:
Following the procedure of Example 1 using 26.9 g of 3-(4-bromobenzoyl)-2-methylenepropionic acid and 10 ml of thiopropionic acid in place of 19.0 g of 3-benzoyl-2-methylenepropionic acid and 8.0 ml of thioacetic acid, respectively, there was obtained 25.5 g (yield: 71%) of 3-(4-bromobenzoyl)-2-propionylthiomethylpropionic acid as crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[C:15]([CH3:21])[C:14]([CH:22]([CH2:28][CH2:29][CH3:30])[C:23]([O:25]CC)=[O:24])=[C:13]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C(O)C>[CH2:1]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[C:15]([CH3:21])[C:14]([CH:22]([CH2:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[C:13]([C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(Cc1ccccc1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(Cc1ccccc1)C3
Yield: 5.6 %

Procedure:
To a suspension of ethyl [7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate (0.514 g; 1 mmol) in a mixture methanol-ethanol (2:1) (15 mL) was added a 5% sodium hydroxide solution (15 mmol; 12 mL) and the reaction mixture was heated at reflux for 18 h. After cooling, the organic volatiles were removed under reduced pressure and the remaining basic solution was acidified with HCl (1N) until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 2) furnished 0.027 g (5.5%) of the title compound as a light yellow solid.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[CH:53]=[C:52]([CH2:54][NH2:55])[N:51]=[CH:50]1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:52]4[N:51]=[CH:50][N:49]([CH3:48])[CH:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cn1cnc(CN)c1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cn(C)cn1
Yield: 74 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-imidazol-4-yl)methanamine, the title compound was obtained as a yellowish solid in 74% yield: 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.87 (s, 1H), 6.28 (t, J=5.0 Hz, 1H), 6.11 (s, 1H), 4.49 (d, J=5.0 Hz, 2H), 4.42 (s, 2H), 3.82-3.74 (m, 2H), 3.66 (s, 3H), 3.46-3.38 (m, 2H), 2.47 (s, 3H): MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OC)[CH:9]=2)=[O:4].Cl.[NH2:28][C@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32].[CH3:42][O-].[Na+]>CO>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:28][C@H:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:30]([OH:34])[C:31]([O:33][CH3:42])=[O:32])=[O:4])[N:6]=1)#[N:26]
Reactant: C[O-]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Reactant: N[C@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 140 °C

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (15 mg, 0.05 mmol), (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid hydrochloride (40 mg, 0.17 mmol) (Yuan et al. (1993) J Med Chem 36:211-220) and NaOMe (18 mg, 0.33 mmol) in MeOH (2 mL) was heated at 140° C. in a microwave for 2 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 4 mg. MS: (−) m/z 496.14 (M−1).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].C1CCCCC1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([S:34][CH2:35][C:36]#[N:37])=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(I)C>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([S:34][CH:35]([C:36]#[N:37])[CH2:1][CH3:2])=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC#N)c2CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCI
Product: CCC(C#N)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of 1.5M lithium diisopropylamide in cyclohexane (1.37 mL, 2.05 mmol) in dry THF (5 mL) at −78° C. under dry nitrogen, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (600 mg, 1.70 mmol) in THF (5 mL) and continue stirring for 2 h. Rapidly transfer the above solution via cannula to a solution of ethyl iodide (13.2 g, 84.9 mmol) in THF (5 mL) and continue stirring for 1 h. Quench with aqueous saturated ammonium chloride solution, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-(1-cyanopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a pale oil (350 mg, 68%). Use a method similar to the General Procedure 1-4 to give the title compound as an off-white solid. MS (ES+) m/z: 281 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[N:44]1([CH2:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])[CH:3]=3)=[CH:37][CH:38]=2)[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: CC1(C)OB(c2ccc(CCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(-c3ccc(CCN4CCOCC4)cc3)c2)c1)NOC1CCCCO1
Yield: 85.8 %

Procedure:
(E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (7.60 g) and 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-morpholin (8.00 g) are dissolved in DME (300 mL). (Ph3P)3PdCl2 (2.40 g) and a 2M Na2CO3-solution (25 mL) are added and the mixture is heated 5 h to reflux temperature under an inert gas atmosphere. The reaction mixture is filtered and evaporated. After addition of a NaHCO3-solution and ethyl acetate, the organic phase is dried and evaporated. The crude product is purified by silica gel flash chromatography. 8.1 g of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O.O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)=[CH:30][CH:31]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccc(Cl)nn3)c2)c2ccc(F)cc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 512 mg; 1.50 mmol), 3,6-dichloropyridazine (450 mg; 3.02 mmol) and K2CO3 (828 mg; 5.99 mmol) in MeCN (15.0 mL) was stirred at 100° C. for 16 hours under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel column chromatography (petroleum ether/EtOAc=4/1 to 2/1) to afford 620 mg (91%) of the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29](=[O:31])[CH3:30])[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH:7]([N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])[CH2:24][CH2:25]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: -78 °C
Yield: 95.1 %

Procedure:
Lithium aluminium hydride (97 mg, 2.56 mmol) was taken up in dry THF (15 ml) and stirred under an inert atmosphere at -78° C. 5-(4-Benzhydrylpiperazin-1-yl)-2-pentanone (717 mg, 2.13 mmol) as a solution in THF (35 ml) was added dropwise. The reaction was stirred at -78° C. for 15 minutes before allowing to warm to room temperature. After a total reaction time of 30 minutes the reaction was quenched with a 15% aqueous solution of sodium hydroxide (25 ml). The reaction mixture was filtered through Kieselguhr gel and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulphate, filtered and solvent removed under reduced pressure to yield (RS)-5-(4-benzhydrylpiperazin-1-yl)-2-pentanol as a white powder (686 mg, 95%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11]2
Reactant: NCCCc1ccccc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(Cl)cccc2CN1CCCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 3-phenyl-propylamine (0.081 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.120 g, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.68 (t, 2H), 3.66 (t, 2H), 4.28 (s, 2H), 7.14-7.44 (m, 8H). GC-MS: m/z 285 (M)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[N+:18]([O-])=O)[CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:18][C:7]1[CH:8]=[C:9]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A mixture of N-(cyclopropylmethyl)-4-(isopropylsulfonyl)-2-nitroaniline (Step D, 521 mg, 1.8 mmol) and 10% palladium carbon (52 mg) in methanol (10 mL) and ethyl acetate (10 mL) was stirred at room temperature for 2 h under hydrogen. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford the title compound (462 mg, 98%) as red brown amorphous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:22]([O:24][C:25](=[O:53])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:29]=1)[CH3:23].Cl>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:53])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][N:37]([CH2:38][CH2:39][CH:40]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:9](=[O:11])/[CH:8]=[CH:7]/[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:29]=1)[CH3:23]
Reactant: CCOC(=O)COc1cccc(CCCNCCC(c2ccccc2)c2ccccc2)c1
Reactant: O=C(O)/C=C/c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CCCN(CCC(c2ccccc2)c2ccccc2)C(=O)/C=C/c2ccncc2)c1
Reaction time: 8 h

Procedure:
To a solution of (2E)-3-(4-pyridinyl)acrylic acid (23 mg) in DMF (1 mL) was added HOBt (21 mg), ethyl(3-{3-[(3,3-diphenylpropyl)amino]propyl}phenoxy)acetate (55 mg) and WSCD.HCl (29 mg) at ambient temperature. The reaction mixture was stirred for 8 hours at the same temperature. The resulting mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=85:15-70:30) to give a ethyl[3-(3-{(3,3-diphenylpropyl) [(2E)-3-(4-pyridinyl)-2-propenoyl]amino}propyl)phenoxy]acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:38]1C=CC=C[CH:39]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10][NH:38][CH3:39])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N([C@H](CCO)c2cccc(F)c2)c2ccccc2C12CCCCC2
Reactant: c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@H](c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 3 h

Procedure:
1′-[(1R)-1-(3-fluorophenyl)-3-hydroxypropyl]spiro [cyclohexane-1,3′-indol]-2′(1′H)-one (0.26 g, 0.74 mmol) was dissolved in pyridine (4 mL) and toluenesufonyl chloride (0.21 g, 1.1 mmol) was added. Stirred for 3 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 30 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 1′-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one as a colorless oil (0.26 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.71 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 203 mg (51% over three steps) 1′-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](COC)=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1>>[O:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17](=[O:21])[O:18]5)=[CH:13][CH:12]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]1=[O:21]
Reactant: COCc1cc(=O)oc2cc(N)ccc12
Reactant: Fc1cnc(Cl)nc1Cl
Product: O=c1ccc2ccc(Nc3ncc(F)c(Nc4ccc5ccc(=O)oc5c4)n3)cc2o1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylcoumarin were reacted to yield N2,N4-bis(coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.38 (s, 1H), 8.42 (d, 1H, J=3 Hz), 8.28 (m, 1H), 8.05-7.93 (m, 2H), 7.77-7.50 (m, 4H), 6.31 (s, 1H), 6.29 (s, 1H), 4.66 (s, 2H), 4.65 (s, 2H), 3.43 (s, 3H), 3.41 (s, 3H); LCMS: MS (m/e): 505 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:26]3[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: CC1CCNCC1
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (200 mg) and 4-methylpiperidine (2 ml) was heated at 120° C. for 8 h to obtain 40 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)ethanone after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=1>>[NH2:35][C:30]1[CH:29]=[C:28]([F:27])[CH:33]=[CH:32][C:31]=1[NH:34][C:24]([C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: Nc1ccc(F)cc1N
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccc(F)cc5N)cccc4c3)ccnc2c1
Yield: 73 %

Procedure:
The title compound (33.1 mg, 73% yield) was prepared as a brown solid from 6-(7-methoxyquinolin-4-yloxy)-1-naphthoic acid (34.5 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.95 (s, 3H, —OCH3), 5.27 (s, 2H, benzene-NH2), 6.41 (td, J=2.5 and 8.4 Hz, 1H, Ar—H), 6.57-6.61 (m, 2H, Ar—H), 7.30-7.36 (m, 2H, Ar—H), 7.45 (d, J=2.2 Hz, 1H, Ar—H), 7.56 (dd, J=2.2 and 9.2 Hz, 1H, Ar—H), 7.65 (t, J=7.6 Hz, 1H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.07 (d, J=8.3 Hz, 1H, Ar—H), 8.24 (d, J=9.1 Hz, 1H, Ar—H), 8.43 (d, J=9.2 Hz, 1H, Ar—H), 8.65 (d, J=5.1 Hz, 1H, Ar—H), 9.75 (s, 1H, benzene-NH). LC-MS (m/z) 454 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>CN(C)C=O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5]
Reactant: CCOC(=O)CCCS
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
Under an argon atmosphere, 2-fluorobenzaldehyde (5 g) was dissolved in 15 ml of dimethylformamide and potassium carbonate (8.35 g) was added. Ethyl 4-mercaptobutyrate (8.6 ml) was added at room temperature and was stirred at room temperature for 14 hours. After the addition of 100 ml of ethyl acetate, the mixture was washed with 50 ml of water twice, 50 ml of a 0.5N hydrochloric acid, and 50 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=4/1) purification. The resulting effective fractions were concentrated to yield ethyl 4-(2-formylphenylthio)butyrate (6.86 g, Yield 67%).