Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:34](=[CH:35][CH:36]=1)[C:12]1[N:13](COCC[Si](C)(C)C)[C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:37][C:38]([OH:41])([CH3:40])[CH3:39])=[CH:6][C:5]2=1>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:34](=[CH:35][CH:36]=1)[C:12]1[NH:13][C:14]([C:16]3[C:17]([C:18]#[N:19])=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]#[N:25])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:37][C:38]([OH:41])([CH3:39])[CH3:40])=[CH:6][C:5]2=1
Reactant: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Yield: 33.2 %

Procedure:
2-(9-chloro-6-(2-hydroxy-2-methylpropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.94 g) from Step 3 above was dissolved in TBAF (1 M in THF, 20 mL). The mixture was heated at reflux for 5 h and then quenched with water. The aqueous layer was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (50% ethyl acetate in hexanes) to provide 2-[9-chloro-6-(2-hydroxy-2-methylpropyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (500 mg) as a yellow solid. 1H NMR δ (ppm)(400 MHz, Acetone-d6): 13.13 (1H, bs), 8.87 (1H, s), 8.77 (1H, s), 8.58 (1H, m), 8.43 (1H, m), 8.35 (2H, d, J=7.9Hz), 7.99 (1H, t, J=7.9 Hz), 7.73 (2H, dd, J=1.9, 8.6Hz), 3.51 (1H, bs), 3.08 (2H, s), 1.26 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[Na+].[Na+]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([OH:16])([C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([F:14])([F:13])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2cnc3ccccc3c2)C(F)(F)F)c(Cl)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 120 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-quinolin-3-yl-butan-2-ol (Example 178, 2.60 g) was suspended in aqueous HBr (48%, 52 ml). The mixture was stirred for 16 h at 80° C., for 20 h at 105° C., for 7 h at 110° C. and for 6 h at 120° C. The reaction mixture was poured into ice water/EtOAc, neutralized with aqueous sat. Na2CO3 solution and extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1=>EtOAc/MeOH 9:1=>1:1) and subsequently precipitated from hot EtOAc to give the title compound (1.83 g) as an off-white solid. MS (m/e)=382.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:25]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 8 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}-2-methylpropan amide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.32–7.24 (m, 7H), 6.91 (d, 1H, J=7.2 Hz), 6.67 (m, 1H), 3.31 (q, 2H, J=5.5 Hz), 2.92–2.85 (m, 2H), 2.53 (septet, 1H, J=6.7 Hz), 2.43 (tt, 1H, J=11.6, 3.0 Hz), 2.33 (t, 2H, J=6.7 Hz), 1.91 (dt, 2H, J=11.7, 1.8 Hz), 1.78–1.72 (m, 2H), 1.65–1.59 (m, 2H), 1.56 (s, 6H), 1.52–1.45 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 484.3 (M+H)+; Anal. Calc. for (HCl salt) C28H38ClN3O2.HCl.0.30 CHCl3: C, 61.10; H, 7.12; N, 7.55. Found: C, 60.90; H, 7.20; N, 7.64.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([OH:8])[CH:4]=1.S(Cl)([Cl:12])(=O)=O>C1C=CC=CC=1>[Cl:12][C:4]1[C:5]([OH:8])=[N:6][O:7][C:3]=1[CH2:2][Cl:1]
Reactant: Oc1cc(CCl)on1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Product: Oc1noc(CCl)c1Cl

Procedure:
To a solution of 8.01 g of 5-chloromethyl-3-hydroxyisoxazole in 50 ml of benzene were added 10 g of sulphuryl chloride, and then the mixture was refluxed for 10 hours. At the end of this time, the solvent and the excess sulphuryl chloride were distilled off from the reaction mixture, and the residue was dissolved in 50 ml of diethyl ether and washed five times, each time with 20 ml of water. The washed diethyl ether solution was dried over anhydrous sodium sulphate, the solvent was removed by distillation, and the residue was extracted three times, each time with 30 ml of hot hexane. The hexane was distilled off from the extract and the residue was recrystallized from carbon tetrachloride, to give 4-chloro-5-chloromethyl-3-hydroxyisoxazole in the form of colourless crystals melting at 116°-118° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2].[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49](=[O:50])[NH2:51])([CH3:53])[CH3:52])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(N)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.2 g) in N,N-dimethylformamide (3 mL) were added 2-amino-2-methylpropionamide (47 mg), 1-hydroxybenzotriazole (50 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg) and triethylamine (0.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.12 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.06 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.1 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (80 mg).
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH:9]=[CH2:10]>[Pt]>[CH3:1][Si:2]([CH3:4])([CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[Cl:3]
Reactant: C=CCCC=C
Reactant: C[SiH](C)Cl
Agent: [Pt]
Product: C=CCCCC[Si](C)(C)Cl

Procedure:
Dimethyl chlorosilane was reacted with an excess 1,5-hexadiene in the presence of a platinum catalyst to form dimethyl-5-hexenylchloro silane. Then indene was reacted with butyl lithium in a mixture of diethyl ether and tetrahydrofuran to produce the indenyl lithium salt which was then reacted with the dimethyl-5-hexenylchlorosilane to yield the omega alkenyl dimethyl indene which can be called 5-hexenyl-dimethyl-silyl-1-indene.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1nncc2cncn12
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CNc2nncc3cncn23)cc1

Procedure:
A solution of 16.6 g of 4-(methylthio)imidazo[1,5-d]-as-triazine, 51.3 ml (50.3 g) of benzylamine and 580 ml of toluene is refluxed for 10 days. After cooling, a precipitate is collected and recrystallized from methanol to yield the desired product, m.p. 275°-278° C.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C:5]1[C:6](=[O:21])[NH:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2].N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH:1]([N:4]([CH3:22])[C:5]1[C:6]([O:21][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(=O)[nH]c2cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (2.0 g, 6.55 mmol) in dichloromethane (80 mL) was added Pyridine (2.0 g, 25.28 mmol) and Tf2O (3.66 g, 12.97 mmol) with stirring overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL) and extracted with dichloromethane (3×80 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (2.50 g, crude), which was used in the next step directly.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:4]([C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)=[N:3]1.[CH:21](=O)[CH2:22][CH3:23].C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:4]([C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH3:23])=[N:3]1
Reactant: Cn1nc([C@H]2CCCN2)c2c3c(c(=O)[nH]c21)CCCC3
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN1CCC[C@@H]1c1nn(C)c2[nH]c(=O)c3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a 250 mL of reaction flask were added the compound of Example 4F (1.39 g, 5.1 mmol), propanal (0.888 g, 15.31 mmol) and methanol (90 mL). The mixture was stirred for 2 hr at room temperature. Sodium cyanoborohydride (1.0 g, 15.9 mmol) was added to the mixture. The reaction was kept overnight with stirring. The reaction was stopped. The product was concentrated by rotary-evaporation and purified by column chromatography to give 1.4 g of the title compound. Yield: 87.5%. MS (ESI): m/z 315 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>O1CCCC1>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CO)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 930 mg of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran was placed at 0° C. in a sulphonation flask and treated within 20 minutes with a solution of 8.2 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxaldehyde in 100 ml of absolute tetrahydrofuran. After completion of the addition, the mixture was stirred for a further 2 hours while warming to room temperature, subsequently cautiously quenched with 100 ml of 1N sulphuric acid and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. There were obtained 7.90 g (96%) of 4'-(trans-4-pentylcyclohexyl)-4-biphenylmethanol as a colourless, crystalline mass (purity 99.4% in accordance with gas chromatography) which was used in the following step without further purification. M.p. 180.4° C.; Rf value [petroleum ether/ethyl acetate (9:1)]: educt 0.70, product 0.30.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:8][CH2:9][CH:10]([CH3:14])[C:11](Cl)=[O:12])=[O:7].C(SCC(C)C(Cl)=O)(=O)C.C(SCC(C)C([N:38]1[CH2:42][CH2:41][CH:40]=[C:39]1[C:43]([OH:45])=[O:44])=O)(=O)C1C=CC=CC=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:8][CH2:9][CH:10]([CH3:14])[C:11]([N:38]1[CH2:42][CH2:41][CH:40]=[C:39]1[C:43]([OH:45])=[O:44])=[O:12])=[O:7]
Reactant: CC(CSC(=O)c1ccco1)C(=O)Cl
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)O
Agent: CC(=O)SCC(C)C(=O)Cl
Product: CC(CSC(=O)c1ccco1)C(=O)N1CCC=C1C(=O)O

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 3-[(2-furanylcarbonyl)thio]-2-methylpropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in part (b) and subjecting the product to the procedure of Example 1(c), one obtains (±)-4,5-dihydro-1-[3-[(2-furanylcarbonyl)thio]-2-methyl-1-oxopropyl]-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C@H:14]2[C@@H:19]3[O:20]C(=O)[O:22][C@@H:18]3[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15]2)[C:10]([CH3:28])=[C:9]2[C:4]=1[CH:5]=[C:6]([NH:30][C:31](=O)[O:32]CC1C=CC=CC=1)[C:7](=[O:29])[O:8]2.CCN=C=NCCCN(C)C.[NH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[C:53]1C(O)=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:20][C@@H:19]1[C@H:18]([OH:22])[C@@H:17]([O:24][CH3:25])[C:16]([CH3:26])([CH3:27])[O:15][C@H:14]1[O:13][C:11]1[C:10]([CH3:28])=[C:9]2[C:4]([CH:5]=[C:6]([NH:30][C:31]([C:53]3[NH:52][C:60]4[C:55]([CH:54]=3)=[CH:56][CH:57]=[CH:58][CH:59]=4)=[O:32])[C:7](=[O:29])[O:8]2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1cc(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)c(C)c2oc(=O)c(NC(=O)OCc3ccccc3)cc12
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(O[C@@H]2OC(C)(C)[C@H](OC)[C@@H](O)[C@H]2O)c(C)c2oc(=O)c(NC(=O)c3cc4ccccc4[nH]3)cc12
Reaction time: 12 h
Yield: 5.1 %

Procedure:
Palladium on carbon (10%, 40 mg) was added to 25d (200 mg, 0.36 mmol) in anhydrous THF (2.40 mL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (150 mg, 99%). EDCI (57.5 mg, 0.30 mmol) and 1H-indole-2-carboxylic acid (38.7 mg, 0.24 mmol) were added to the amine (50.6 mg, 0.12 mmol) in 30% pyridine/CH2Cl2 (3.30 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (26.3 mg, 39%). Triethylamine (150 μL) was added to the carbonate (26.3 mg, 0.047 mmol) in MeOH (2.00 mL) and CH2Cl2 (2.00 mL). After 48 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26l as a colorless amorphous solid (6.60 mg, 26%, 10% over 3 steps): 1H NMR (CD2Cl2, 400 MHz) δ 9.26 (s, 1H), 8.96 (s, 1H), 8.68 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.38-7.34 (m, 1H), 7.22-7.16 (m, 1H), 6.84 (s, 1H), 6.00 (s, 1H), 5.65 (d, J=1.7 Hz, 1H), 4.26-4.21 (m, 2H), 3.96 (s, 3H), 3.59 (s, 3H), 3.35 (d, J=8.6 Hz, 1H), 2.25 (s, 3H), 1.53 (s, 3H), 1.20 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 165.1, 157.4, 156.5, 149.7, 136.7, 134.7, 127.7, 125.3, 122.5, 121.1, 120.0, 111.9, 104.6, 103.8, 97.7, 94.0, 84.3, 84.2, 82.6, 69.6, 69.1, 66.1, 62.2, 62.0, 59.7, 23.1, 22.7, 14.2; IR (film) νmax 3389, 2924, 2853, 1697, 1605, 1535, 1460, 1340, 1211, 1101, 1088, 962, 729 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C28H30N2O9, 539.2030. found, 539.2056.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14](Cl)[CH3:15])[C:10](=[O:12])[CH3:11].[CH3:17][NH:18][CH3:19].C1C=CC=CC=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14]([N:18]([CH3:19])[CH3:17])[CH3:15])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)N(CC(C)Cl)c1c(C)cccc1C
Reactant: CNC
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A mixture of 3.0 g (12.5 mmoles) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2-chloro-propane and 9.4 ml of a 18 w/v % ethanolic dimethylamine solution is heated at 60° C. for 3 hours in a bomb. The mixture is cooled, admixed with 50 ml of benzene and 10 ml of water, and the organic phase is separated. The aqueous phase is extracted twice with 10 ml of benzene, each. The benzene solutions are combined, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 2.8 g (90.3%) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2dimethylamino-propane are obtained as a thick, light yellow oil; b.p.: 140°-141° C./120 Pa. The hydrochloride monohydrate of the base melts at 170°-172° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)CC#N)cc2)cc1
Reactant: O=C1CCCCC1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)C(C#N)=C3CCCCC3)cc2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a mixture of 54.0 g of methyl 4-(2-{4-[(cyanoacetyl)amino]phenyl}ethyl)benzoate, 50.0 mL of cyclohexanone, and 300 mL of toluene was added dropwise 15.0 mL of morpholine at room temperature. In a reaction apparatus to which a Dean-Stark type dehydration tube was attached, the reaction mixture was stirred at 120° C. for 3 hours. Subsequently, the reaction mixture was further heated to reflux and stirred for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue was further added 200 mL of diisopropyl ether, followed by stirring for 14 hours. The precipitated solid was collected by filtration to obtain 53.2 g of methyl 4-[2-(4-{[cyano(cyclohexylidene)acetyl]amino}phenyl)ethyl]benzoate as a beige solid. ESI+: 403
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:34])[CH:32]=2)[NH:27][N:26]=1>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:34][C:31]4[CH:32]=[C:33]5[C:28](=[CH:29][CH:30]=4)[NH:27][N:26]=[C:25]5[CH3:24])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CC(C)O
Product: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)cc12
Temperature: 90 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50.1 mg, 0.150 mmol) and 3-methyl-1H-indazol-5-ylamine (25.0 mg, 0.170 mmol) in iPrOH (2.5 mL) in a sealed tube was heated to 90° C. (bath temp.) for 16 h. The solvent was evaporated, water/NaHCO3 solution was added, the mixture was extracted with CH2Cl2 (3×30 mL), and the combined extracts were washed with brine and dried over MgSO4. The extracts were filtered through a pad of silica gel, washing with 5% MeOH in CH2Cl2 until no more product eluted as indicated by TLC. Concentration in vacuo gave a light brown solid. The solid was triturated with MeOH, filtered, washed with more MeOH, and dried in vacuo overnight. One obtained the title compound as white solid, mp. 245-250° C. (decomp.). 1H NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.42-2.50 (brs, 2H), 2.47 (s, 3H), 3.53-3.59 (me, 2H), 3.99-4.08 (m, 2H), 6.38 (brs, 1H), 6.73 (brs, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.69 (dd, J=1.6, 8.8 Hz, 1H), 8.15 (s, 1H), 8.23 (s, 1H), 9.32 (s, 1H), 11.88 (brs, 1H), 12.54 (s, 1H). MS (ES+): m/z 446.0 (100) [MH+]. HPLC: tR=2.4 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:37])[F:38])(=[O:35])=[O:34])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and 2-trifluoromethyl-benzenesulfonyl chloride (146 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 mL, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). Then, the organic compound was extracted into ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified by using an ISCO (40 g) column chromatography eluting with 5-30% ethyl acetate in hexanes to afford {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (132 mg, 82%) as a light yellow foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H), 8.16 (d, J=7.2 Hz, 1 H), 8.03 (dd, J=7.2, 1.7 Hz, 1 H), 7.82-7.96 (m, 4 H), 7.45 (dd, J=8.8, 1.6 Hz, 1 H), 7.25 (d, J=8.5 Hz, 2 H), 7.12 (d, J=8.5 Hz, 2 H), 6.95 (d, J=1.6 Hz, 1 H), 3.92 (s, 2 H), 3.63 (s, 3 H), 1.98 (s, 3H). HRMS calcd. for C27H20ClF3NO4S [(M−H)−] 546.0759, obsd. 546.0762.