Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:9]([C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]=[CH:33][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:30][CH:31]=2)=[CH:20][CH:19]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(I)cc1
Reactant: C=Cc1ccc(C=Cc2ccc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C=Cc2ccc(C=Cc3ccc(C=Cc4ccccc4)cc3)cc2)cc(C(C)(C)C)c1
Temperature: 90 °C
Yield: 71 %

Procedure:
A 50 mL round bottom flask was charged with a Teflon coated stir bar, 4-iodophenylmethane (408 mg, 2.0 mmol), 1-(3′5′-di-tert-butylstyryl)-4-(4′-vinylstyryl)benzene (0.84 g, 2.0 mmol), Pd(OAc)2 (22.45 mg, 0.1 mmol), K2CO3 (690 mg, 5.0 mmol), n-Bu4NBr (665 mg, 2.0 mmol) and DMF (16 mL). The mixture was degassed with 4 freeze-pump-thaw cycles and heated at 90° C. for 48 hours. The reaction was cooled to room temperature, diluted with CH2Cl2, washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified on a silica gel column (20% CH2Cl2/hexanes) to give a yellow greasy solid which contains cis-trans isomers. The isomers were dissolved in 150 mL benzene and degassed with 4 freeze-pump-thaw cycles. The solution was irradiated with Blak-Ray long UV lamp for 60 minutes and the solvent was removed under reduced pressure. The isomerized product was repurified on a silica gel column (20% CH2Cl2/hexanes) to give a yellow solid (yield 71%). 1H NMR (CDCl3): δ 7.51-7.54 (overlapping signals, 9H), 7.35-7.39 (overlapping signals, 5H), 7.28 (t, J=7.50 Hz, 1H), 7.19 (d, J=16.3 Hz, 1H), 7.13 (complex, 4H), 7.10 (d, J=16.3 Hz, 1H), 1.37 (s, 18H). 13C NMR (CDCl3): δ 151.28, 137.54, 136.66, 129.96, 128.93, 128.78, 128.49, 128.20, 127.76, 127.09, 127.04, 127.01, 126.73, 121.09, 31.69. Exact Mass (FAB, NBA) for M+ (C38H40): calculated 496.3143; found 496.3189.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[NH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:26])[N:24]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N)n1
Yield: 62.6 %

Procedure:
The compound was prepared using the method of Example 34(d). (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g; 3.84 mmol), 2-aminothiazole-4-carboxylic acid (0.66 g; 4.66 mmol), 1.00 ml of DIPEA, HOBt (0.26 g; 1.9 mmol) and EDCI (1.10 g; 5.75 mmol) were used as starting materials. Purification by isopropanol:toluene crystallization afforded 0.93 g (63%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.10 (d, 3H), 4.22-4.45 (m, 3H), 6.96 (d, 1H), 7.04 (broad s, 2H), 7.15 (s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.97 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([Br:13])=[CH:4][N:3]=1.[CH3:14][C:15]1[C:23]2[C:22](=[O:24])[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19][C:18]=2[NH:17][CH:16]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:17]3[C:18]4[CH2:19][C:20]([CH3:25])([CH3:26])[CH2:21][C:22](=[O:24])[C:23]=4[C:15]([CH3:14])=[CH:16]3)=[CH:9][CH:10]=2)[C:5]([Br:13])=[CH:4][N:3]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Nc1ncc(Br)c2cc(F)ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(N)ncc(Br)c3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 24.7 %

Procedure:
To a solution of 1-amino-4-bromo-6-fluoro-isoquinoline (0.029 g, 0.12 mmol) in DMF (1 mL) are added 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.042 g, 0.24 mmol) and NaH (0.01 g, 0.24 mmol). The reaction mixture is microwaved at 120° C. for 40 min, cooled to RT, and treated with NH4Cl (satd. aq, 2 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-10% MeOH/CH2Cl2) affords 0.0118 g (25%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one. LC/MS m/z=399 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:16]=[C:15]([CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[CH:22][N:21]=3)[CH:13]=2)[N:8]=1>O1CCOCC1>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]#[C:18][C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:16]=[C:15]4[CH3:17])=[N:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Solvent: C1COCCO1
Product: Cc1cc(N2CCCC2)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
77 μL (0.925 mmol) of pyrrolidine is added to a solution of 90 mg (0.231 mmol) of 2-chloro-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline in 5 mL of 1,4-dioxane and the reaction mixture is refluxed overnight. It is evaporated down in vacuo, and the residue is taken up in DMF and purified by HPLC-MS. The fractions containing the product are combined, evaporated down, and freeze-dried. The product is dissolved in DCM, evaporated down, and the residue is triturated with a little EtOAc, filtered, washed again with a little EtOAc, and dried at 50° C. in the circulating air dryer. Yield: 39 mg (39% of theoretical); C27H22ClN3 (M=423.936); calc.: molpeak (M+H)+: 424/426 (Cl); found: molpeak (M+H)+: 424/426 (Cl); HPLC-MS: 5.8 min (method A).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Product: CC(=O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Yield: 90.4 %

Procedure:
The compound was also accessible, inter alia, by first reacting 7-benzyl-3-methylxanthine with 1-chloro-5-hexanone under the reaction conditions described above to give 7-benzyl-3-methyl-1-(5-oxohexyl)-xanthine (yield 90.4% of theory, melting point: 82°-84° C.) and then reductively methylating the oxohexyl side chain with methylmagnesium chloride in anhydrous ether analogously to Example 9 (yield: 60.2% of theory; melting point: 108°-110° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)C1(CI)CCOCC1
Agent: [K+]
Solvent: O
Product: COC(=O)C1(CSC(C)=O)CCOCC1
Reaction time: 18 h
Yield: 97 %

Procedure:
4-Iodomethyltetrahydropyran-4-carboxylic acid methyl ester (3.05 g) was dissolved in NN-dimethylformamide (20 ml) at room temperature and potassium thioacetate (1.47 g) added. The mixture was stirred for 18 hours then diluted with water (50 ml) and extracted with diethyl ether (4×25 ml). The combined organics were washed with saturated sodium bicarbonate solution (3×20 ml) and brine (20 ml), then dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound as a yellow solid (2.42 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH2:4][OH:5])=[C:2]([NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(F)ccc1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1cc(F)ccc1CO
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a solution of 2-amino-4-fluorobenzyl alcohol from Step 1 (2.00 g, 14.17 mmol) and methylene chloride (45 mL), was added N,N,-diisopropylethylamine (3.70 g, 28.34 mmol) followed by hydrocinnamoyl chloride (4.78 g, 28.34 mmol) dropwise over 15 min under an argon atmosphere at 23° C. After 16 h, the reaction was diluted with methylene chloride (100 mL), washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was dissolved in methanol (14 mL) and NaOH (1.5 N, 14 mL) was added at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[5-fluoro-2-hydroxymethylphenyl]benzenepropanamide (3.40 g, 87.8%) as an oil: 1H NMR (CDCl3) δ 2.65 (t, J=7 Hz), 3.05 (t, J=7 Hz), 4.48 (s), 6.68-6.74 (m), 7.00-7.34 (m), 7.83-7.91 (m) 8.72 (br s). MS (EI) 273, 255, 212. IR (neat) 3500-3150, 1667 cm−1. Anal. Calc'd. for C16H16NO2F: C, 70.31; H, 5.90; N, 5.13. Found: C, 70.26; H, 6.11; N, 5.03.
Reaction SMILES: [CH:1]([CH:4]([C:10]([CH3:12])=O)[C:5]([O:7]CC)=O)([CH3:3])[CH3:2].[F:13][C:14]([F:19])([F:18])[C:15]([NH2:17])=[NH:16].O(C)[Na]>CO>[CH3:12][C:10]1[N:16]=[C:15]([C:14]([F:19])([F:18])[F:13])[NH:17][C:5](=[O:7])[C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Reactant: N=C(N)C(F)(F)F
Agent: CO[Na]
Solvent: CO
Product: Cc1nc(C(F)(F)F)[nH]c(=O)c1C(C)C
Yield: 63.6 %

Procedure:
Ethyl 2-isopropylacetoacetate (35.8 mL, 0.2 mol) was mixed with trifluoroacetamidine (23 g, 0.2 mol) in MeOH, and then NaOCH3 (21.6 g, 0.4 mol) was added. The mixture was refluxed for 18 h then evaporated to dryness. The residue was taken up in H2O (200 mL) and extracted with ether. The aqueous solution was reduced in volume and acidified with acetic acid to pH 5 then extracted with EtOAc. The combined organic extracts were washed with a small quantity of water, dried over Na2SO4, then evaporated to afford 28 g of an oil. The crude product was purified by flash chromatography (CHCl3) to provide 16 g (36% yield) of pure compound.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[N+](C)(C)C.C(O)(=O)C(C)C.[C:18](=[O:28])([S:26][CH3:27])[O:19][O:20][CH:21](Cl)[CH:22]([CH3:24])[CH3:23]>CCOC(C)=O>[C:18](=[O:28])([S:26][CH3:27])[O:19][O:20][CH:21]([O:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)[O-]
Reactant: CSC(=O)OOC(Cl)C(C)C
Agent: C[N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)C(=O)O
Product: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Temperature: 80 °C
Yield: 67.7 %

Procedure:
To a 3 L three neck round bottom flask equipped with a mechanical stirrer and teflon-coated thermocouple was added compound (13) (1672 g, 9 mol), isobutyric acid (264 g, 1.5 mol), and compound (12) (1050 g, 5.76 mol). The reaction mixture was heated to 80° C. for 12 h and the progress of the reaction monitored by 1H NMR. The reaction mixture was cooled to 20° C., diluted with EtOAc (1 L) and sequentially washed with water (2×1 L), saturated NaHCO3 (1×2 L), and water (1 L). The organic phase was separated and concentrated under reduced pressure to afford the title compound (11) (905 g, 3.9 mol, 65% yield) as a colorless liquid. 1H NMR (CDCl3, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H), 2.05 (m, 1H), 2.35 (s, 3H), 2.6 (m, 1H), 6.7 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][CH2:32][CH:33](O)[CH2:34][CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH:33]([CH2:34][CH3:35])[CH2:32][CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: CCC(O)CC
Product: CCC(CC)OC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and pentan-3-ol according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.38 Hz, 6H), 1.18-1.63 (m, 7H), 1.64-1.81 (m, 4H), 1.96 (ddd, J=26.11, 12.96, 4.16 Hz, 1H), 2.06-2.18 (m, 1H), 2.23-2.40 (m, 1H), 2.83-3.01 (m, 1H), 3.07-3.18 (m, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H), 4.64 (dd, J=9.67, 5.37 Hz, 1H), 5.04 (dt, J=12.35, 6.18 Hz, 1H), 7.03 (dd, J=8.86, 2.15 Hz, 1H), 7.30 (d, J=2.15 Hz, 1H), 7.46 (d, J=8.86 Hz, 2H), 7.84-7.99 (m, 2H), 8.15 (d, J=8.06 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:32]=[C:31]([I:33])[CH:30]=[CH:29][C:27]=1[NH2:28]>O1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:28][C:27]2[CH:29]=[CH:30][C:31]([I:33])=[CH:32][C:26]=2[F:25])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Reactant: Nc1ccc(I)cc1F
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Yield: 54.9 %

Procedure:
4-Chloro-1-(4-methoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.8 g, 5.2 mmol) and 2-fluoro-4-iodoaniline (1.5 g, 6.3 mmol) were dissolved in dioxane (20 mL) and the resultant mixture stirred at reflux for 16 hours. The reaction mixture was diluted with water (50 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic fractions were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-30% ethyl acetate in cyclohexane) to yield the title compound as a white solid (1.56 g, 56%). LCMS (Method B): RT=4.78 min, [M+H]+=547.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29]CC4C=CC=CC=4)=[CH:22][C:21]=3[O:37][CH3:38])[N:11]=2)[CH2:6][CH2:5]1)[CH3:3]>CO.[Pd]>[CH2:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][C:21]=3[O:37][CH3:38])[N:11]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: CCN1CCN(c2nc(-c3ccc(OCCOCc4ccccc4)cc3OC)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(OCCO)cc3OC)cc3ccccc23)CC1
Yield: 52.4 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethoxy)-2-methoxyphenyl]isoquinoline hydrochloride (0.10 g) was dissolved in methanol (20 ml), followed by the hydrogenation in the presence of 10% palladium/carbon catalyst (0.03 g) at room temperature for 6 hr. The catalyst was filtered off. The resulting solution was washed with methanol, and then the filtrate was evaporated. The resulting residue was crystallized from ethanol/ether, to give the title compound (0.04 g) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:41][N:42]([CH3:47])[CH2:43][C:44]([O:33][C@@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:45]
Reactant: CN(C)CC(=O)O
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)CN(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a mixture of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydro-xylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.54 g, 1 mmol), N,N-dimethylglycine (0.206 g, 2 mmol, Alfa) and DMAP (0.244 g, 2 mmol, Aladdin) in 15 mL of CH2Cl2 at 0° C. was added EDC solid (0.575 g, 3 mmol, Aladdin) in portions. The mixture was continued to stir at 0° C. for 2 hrs, then the reaction mixture was warmed up to room temperature and stirred at rt for 20 hrs. The reaction mixture was diluted with 100 mL of CH2Cl2 and washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 (20 mL×2) and water (20 mL×8), and the aqueous phase was extracted with EtOAc(15 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a yellow solid (0.387 g, 61.6%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([NH:14]C(=O)C)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH:18]S(O)(=O)=O.N([O-])=O.[Na+].NC(N)=O>O>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([OH:18])[CH:3]=1
Reactant: CC(=O)Nc1ccc(C2CCCCC2)c(N)c1
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C2CCCCC2)c(O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
N-(3-amino-4-cyclohexyl-phenyl)acetamide (696 mg, 3.0 mmol) was added dropwise to a mixture of conc. H2SO4 (3 mL, 56.28 mmol) and H2O (17 mL). This reaction mixture was cooled to 0° C. and a solution of NaNO2 (229 mg, 3.32 mmol) in H2O (2 mL) was added. The reaction mixture was stirred for 5 minutes at 0° C. and then 1 g of urea was added, followed by the addition of 10 mL of 1:2 H2SO4:H2O. The reaction mixture was then refluxed for 1 hour, cooled to room temperature and extracted with EtOAc. The aqueous layer was basified with solid NaOH and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to obtain 5-amino-2-cyclohexylphenol (426 mg, 74%), which was used without further purification.
Reaction SMILES: [OH-].[K+].C([O:6][C@H:7]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:9](=[CH:10][CH2:11][C@H:12]3[C@H:20]4[C@@:16]([CH:25]=[CH:26][Cl:27])([C@@H:17]([O:21]C(=O)C)[CH2:18][CH2:19]4)[CH2:15][CH2:14][C@@H:13]32)[CH2:8]1)(=O)C>CO>[Cl:27][CH:26]=[CH:25][C@:16]12[CH2:15][CH2:14][C@@H:13]3[C@:28]4([CH3:31])[C:9](=[CH:10][CH2:11][C@H:12]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[OH:21])[CH2:8][C@@H:7]([OH:6])[CH2:30][CH2:29]4
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C=CCl)CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C=CCl)CC[C@@H]12
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
After adding 66 ml of a 10% strength aqueous potassium hydroxide solution, a solution of 1.68 g of 3β,17β-diacetoxy-13-(2-chlorovinyl)-10-methyl-gon-5-ene (a mixture of the cis and trans isomers in a ratio of 1:3) in 132 ml of methanol is stirred for 90 minutes at 45° C whilst passing nitrogen through the mixture. The reaction mixture is then concentrated to about 40 ml in a water pump vacuum and taken up in ethyl acetate. The organic phase, which is separated off, is washed with 1 N hydrochloric acid and with water until neutral, dried and evaporated. Chromatography on silica gel using a mixture of hexane/ethyl acetate (2:1) as the eluant gives 13-(2-chlorovinyl)-10-methyl-gon-5-ene-3β,17β-diol (a corresponding mixture of the cis and trans isomers) in an amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH3:25][CH:24]([CH3:26])[CH2:23][CH2:22][N:21]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CC(C)CCNCCC(C)C
Product: Cc1ccc(-c2oncc2C(=O)N(CCC(C)C)CCC(C)C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and diisoamylamine (9.4 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.7 mg). Calcd for C21H30N2O2: 342.2307, found 342.2318.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[BrH:16].O.N>O>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[C:3]=1[Br:16]
Reactant: Nc1ccc2c(ccc3ccccc32)c1
Reactant: Br
Agent: N
Solvent: O
Product: Nc1ccc2c(ccc3ccccc32)c1Br
Temperature: 25 °C
Yield: 89.5 %

Procedure:
First, 10.0 g of 2-aminophenanthrene were dissolved in 75 mL of N,N-dimethyl sulfoxide, and then 8.3 g of 48% hydrobromic acid were dropped to the solution over 4 hours while the solution was stirred at room temperature. The mixture was continuously stirred at room temperature for 20 hours, and was then stirred at 100° C. for 1 hour under heat. After having been cooled to room temperature, the reaction solution was poured into 300 mL of water. After the mixed solution had been neutralized with ammonia water, the crystal was separated by filtration. The resultant solid was recrystallized with ethanol and water. Thus, 12.6 g of a colorless crystal were obtained (in 90% yield).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[C:37]([CH:38]=[CH:39][CH:40]=2)[C:35]#[N:36])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C#N)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and 3-cyanophenylboronic acid (52 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 92%).