Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (1.43 ml) and dimethylformamide (2 drops) were added to a solution of (R)-(+)-4-(1-benzyloxycarbonylaminoethyl)-benzoic acid (2 g) in dichloromethane (20 ml), and the mixture was refluxed under heating for 1 hour. Afterthe reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml) and the solution was dropwise added to a solution of 4-aminopyridine (525 mg) and diisopropylethylamine (1.17 ml) in acetonitrile (20 ml) under ice-cooling, which was followed by stirring at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate-hexane to give 1.87 g of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)benzamide.
Reaction SMILES: F[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.[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=1)#[N:13]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
4-fluoro-1-naphthonitrile (13916-99-9) (1.0 g, 5.84 mmol) was mixed together with H-D-Thr-OH (835 mg, 7.01 mmol) in DMSO (20 mL). K2CO3 (1.61 g, 11.68 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc and then with EtOAc, 100% to get the pure final product (1.1 g): 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.25 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.84 (d, J=9 Hz, 1H), 7.75 (t, J=9 Hz, 1H), 7.65 (t, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 6.32 (d, J=9 Hz, 1H), 4.53 (m, 1H), 4.38 (m, 1H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(N)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred mixture of 2-chloro-4-methyl-6-nitroaniline (7.39 g, 39.7 mM) and concentrated sulfuric acid (6.2 mL) in absolute ethanol (50 mL) at 0°-5° C. was slowly added a solution of sodium nitrite (6.85 g, 99.3 mM) in water (6 mL). The temperature of the reaction mixture was not allowed to exceed 5° C. during the addition. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 hr and then at reflux until the evolution of gas from the reaction mixture ceased. The reaction mixture was allowed to cool and was concentrated. The residue was slurried with ether and then filtered to remove the solids. The liltrate was concentrated and the residue chromatographed (eluant: diethyl ether/hexane; 1/9) to provide (6.25 g, 92%) the title compound as a yellow crystalline solid, mp 60.5°-61° C.; MS(CI): 172 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([OH:7])=O.O[NH:18][C:19](=[NH:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:28]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Temperature: 132.5 °C
Reaction time: 2 h

Procedure:
N,N-Dicyclohexylcarbodiimide (0.615 g, 0.003 mol) is added to a solution of 3-chloro-4-cyclohexyl benzoic acid (0.475 g, 0.002 mol), N-hydroxy-4-hydroxymethylbenzamidine (0.45 g, 0.003 mol) and N-hydroxybenzotriazole monohydrate (0.457 g, 0.003 mol) in N,N-dimethylformamide (10 mL). The reaction mixture is stirred at 130-135° C. for 2 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×20 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (3×15 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 15:85) to give {4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]phenyl}methanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([NH2:19])=[N:15][NH:16][C:17]=1[NH2:18].[C:20](OC)(=[O:26])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+]>CO>[NH2:18][C:17]1[C:13]([CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[CH3:1])=[C:14]2[NH:19][C:20](=[O:26])[CH2:21][C:22](=[O:23])[N:15]2[N:16]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1c(Cc2c(N)n[nH]c2N)cccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cc2c(N)nn3c2NC(=O)CC3=O)cccc1C(F)(F)F
Temperature: 65 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a solution of 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-3,5-diamine (1 g, 3.70 mmol), dimethyl propanedioate (1.467 g, 11.10 mmol) in methanol (30 mL) was added sodium methoxide (0.680 g, 12.58 mmol). The reaction mixture was stirred at 65° C. for 18 h. After the reaction mixture was cooled to room temperature, the solvent was evaporated. Water (10 mL) was added in. The mixture was neutralized with 1 N HCl. Filtration gave the product (1.2 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H) 3.59-3.67 (s, 2H) 3.73 (s, 2H) 5.64 (br. s., 2H) 7.14 (d, J=7.83 Hz, 1H) 7.30 (m, 1H) 7.54 (d, J=7.83 Hz, 1H) 11.26 (s, 1H); LC/MS: MS (ES+) m/e 339.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[CH:4]=[O:5].[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[NH:20][N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O.[Cu]I>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:6]1[CH:7]=[CH:8][N:9]=[C:2]([Cl:1])[C:3]=1[CH:4]=[O:5])[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3ccnc(Cl)c3C=O)ncc2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
In a 50 mL round-bottomed flask, 2-chloro-4-iodonicotinaldehyde (389 mg, 1.45 mmol, Eq: 1.6), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (200 mg, 908 μmol, Eq: 1.00) and potassium carbonate (251 mg, 1.82 mmol, Eq: 2) were combined with DMSO (8 ml) to give a yellow solution. The solution was degassed for 5 min with argon. Copper(I) iodide (173 mg, 908 μmol, Eq: 1.00) was added. The reaction mixture was heated to 110° C. and stirred for 2 h and the reaction was allowed to cool to room temperature. The reaction was diluted with 1:1 H2O/sat. NH4Cl (80 mL) and the resulting solid collected by filtration. The solid was washed several times with 1:1 H2O/sat. NH4Cl, then water (2×) and then EtOAc:hexanes (3:1, 2×). A lot of color in the organic phase. A brown solid remained. Solid was washed with EtOAc and then CH2Cl2 several times. The combined organic extracts were washed with water, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 40 g, 5% to 30% EtOAc in hexanes) to afford the desired product (170 mg) as a white solid. (M+H)+=360 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 7.40-7.65 (m, 3 H) 8.24 (d, J=2.64 Hz, 1 H) 8.66 (d, J=5.29 Hz, 1 H) 10.32 (s, 1 H).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[C:17]1([S:23][C:24]2[CH:25]([CH3:48])[C@@H:26]3[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([C:24]2[CH:25]([CH3:48])[C@@H:26]3[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])=[O:2])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: CC1C(Sc2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1C(S(=O)c2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
19 ml of saturated aqueous sodium bicarbonate solution and a solution of 350 mg of 3-chloroperbenzoic acid in 10 ml of methylene chloride were added to a solution of 360 mg of p-nitrobenzyl(1RS,5S,6S)-2-phenylthio-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate in 19 ml of methylene chloride, kept at 0° to 5° C. with ice-water cooling, and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was then diluted with methylene chloride and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by chromatography on a column of silica gel, using a 1/8 mixture of benzene and ethyl acetate as eluent, giving 200 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCCC2)c1
Yield: 67.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(pyrrolidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol) and pyrrolidine (0.042 mL; 0.5 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.037 g (67%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[CH3:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-methylbenzenesulfonyl chloride as starting materials in 18% yield. LCMS for C31H33ClN7O3S (M+H)+: m/z=618.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[O:24][N:23]=1>>[F:33][C:31]1[CH:32]=[C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][CH:2]([CH3:19])[CH3:1])[N:26]=2)[CH:28]=[C:29]([F:34])[CH:30]=1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.3 Hz, 1H), 7.56 (m, 3H), 7.05 (t, J=8.5 Hz, 1H), 6.63 (s, 1H), 5.46 (s, 2H), 2.83 (d, J=7.1 Hz, 2H), 2.13 (m, 1H), 1.07 (d, J=6.6 Hz, 6H); MS (ES) m/z 461 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[CH3:34][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:19][CH:20]=2)[N:4]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 36 %

Procedure:
The thus obtained methyl {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate was dissolved in THF (6 mL) and treated with 1N NaOH (3 mL). The biphashic reaction mixture was stirred at room temperature for 14 hours and then Et2O was added. The organic layer was siphoned off and the remaining aqueous layer was neutralized with 6N HCl. The separated solids was collected by suction, triturated with diisopropyl ether, and filtered to give {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.047 g, 36% yield).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:18]=[CH:17][S:16][C:15]=1[S:19]([N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)(=[O:21])=[O:20]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:4][C:3]=2[O:2]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=S(=O)(c1sccc1Br)n1cccc1
Product: O=S(=O)(c1sccc1-c1ccc2c(c1)OCO2)n1cccc1
Yield: 90 %

Procedure:
N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 13C using 3,4-methylenedioxyphenylboronic acid and N-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purified by flash column chromatography on silica gel using 2% EtOAc in hexane as the eluent resulting in N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole in a 90% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:52][NH:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:53]([CH3:52])[CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCc1ccccn1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (11.2 g, 40 mmol), 1-hydroxy-7-azabenzotriazole (5.4 g, 40 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred for 15 min. Ethyidiisopropylamine (6.85 mL, 40 mmol) and 2-(2-methylaminoethyl)pyridine (5.54 mL, 40 mmol) were added. The reaction mixture was stirred for 16 h. The reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (3×150 mL). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 10.9 g of N-methyl-N{(1R)-1-[N-methyl-N-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([Sn](CCCC)(CCCC)C(C)=C)[CH2:19][CH2:20]C>O1CCOCC1.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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[C:19]([CH3:20])=[CH2:18])[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(C)c1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 105 °C

Procedure:
A mixture of 1-(2-bromo-4-nitrophenyl)-4-methylpiperazine (0.810 g, 2.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.094 g, 0.081 mmol), and tributyl(prop-1-en-2-yl)stannane (0.983 g, 2.97 mmol) in 1,4-dioxane (30 mL) was degassed and heated at 105° C. overnight. After cooling, the suspension was filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=5)[C:31]([CH3:40])=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=5)[C:31]([CH3:40])=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To 2 mL of a chloroform solution containing 109 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 67 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-6-methoxyquinolin-2(1H)-one as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)CO1
Yield: 58 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.1) with 3,5-dichlorophenylboronic acid yielded the title compound (58% yield) as a pale yellow solid. MS (ISP): m/z=399.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:18]1([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 41.6 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.08 g (20 mmole) of iodobenzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 1.6 g (46%) of 2-phenyl-indene.