Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[OH:2][CH2:1][C@H:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1
Reactant: C[C@]12CCCCC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7β-Hydroxymethylandrostane-3,17-dione II-aw was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7β-hydroxymethylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.70-3.60 (2H, m), 3.54 (1H, t), 2.50-0.90 (21H, m), 1.06 (3H, s), 0.86 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23](O)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:39]1([NH:42][C:23](=[O:24])[C:22]2[CH:26]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:28]=[C:20]([NH:19][C:6]3[C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:7]=3[CH3:18])[CH:21]=2)[CH2:41][CH2:40]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)NC2CC2)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure U by stirring 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoic acid (0.030 g, 0.065 mmol), DMAP (0.016 g, 0.131 mmol), EDC (0.025 g, 0.131 mmol), cyclopropylamine (6.46 μL, 0.092 mmol), and DCM (0.6 mL) at 23° C. for 1 hour. Purification by reverse-phase HPLC afforded N-cyclopropyl-3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.71 (1H, m), 8.61 (1H, s), 8.24 (1H, d, J=4.3 Hz), 8.08 (1H, dd, J=9.3, 6.2 Hz), 7.99 (1H, dd, J=7.6, 1.8 Hz), 7.85-7.89 (1H, m), 7.74 (1H, dd, J=10.4, 2.7 Hz), 7.45-7.51 (2H, m), 6.82-6.84 (1H, m), 6.59-6.61 (1H, m), 6.44 (1H, t, J=2.2 Hz), 3.68-3.74 (4H, m), 3.04-3.09 (4H, m), 2.76 (1H, m), 2.18 (3H, s), 0.60-0.69 (2H, m), 0.51 (2H, dd, J=4.2, 2.2 Hz). Mass Spectrum (ESI) m/e=498.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH:15]([NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:37][CH3:38])[CH:11]=1
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C(CN)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile B was then dissolved in ethanol (60 ml) and hydrazine hydrate (2 g) was added. The solution was heated to 60-70 degrees C. for 1.5 hours. TLC showed reaction was complete. The suspension was filtered to remove by-product and the ethanol removed in vacuo. The residue was submitted to flash chromatography on silica gel (ethyl acetate: 2N NH3 in methanol, 9:1) to yield 372 mg of 4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D (100%). 1NMR(CDCl3): 7.3-7.45 (m, 7H), 6.32 (m, 3H), 6.5 (d, 2H), 5.52 (d, 1H), 4.3 (q, 1H), 3.83 (s, 3H), 3.08 (m, 2H), 1,95 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([Cl:30])=[N:13][C:14]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:15][C:16]=1[CH2:17][CH3:18]>CN(C)C=O>[ClH:30].[CH3:10][C:11]1[C:12]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:13][C:14]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: Cc1cc(F)ccc1N
Reactant: CCc1nc(N2CCc3ccccc3C2C)nc(Cl)c1C
Solvent: CN(C)C=O
Product: CCc1nc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2C)c1C
Product: Cl
Yield: 41 %

Procedure:
After 2-methyl-4-fluoroaniline(0.42 ml, 3.8 mmol) was added to a mixture solution of 5-methyl-6-ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.6 g, 2.0 mmol) and dimethylformamide(10 ml), 0.35 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CC(C)=O>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(C)(C)c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of bisphenol A (sigma-Aldrich), 36.35 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and the homogeneous mixture thus obtained was refluxed. During the refluxing, 8.33 ml of allyl bromide (Sigma-Aldrich) was added in a dropwise manner and allowed to react overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. The solvent was evaporated to obtain a coarse product. A target product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 4-(2-(4-(allyloxy)phenyl)propane-2-yl)phenol. The reaction scheme of the 1st step and the NMR data of the intermediate product (11) thus obtained are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[NH:10])=[CH:4][CH:3]=1.[O-][CH2:13][CH3:14].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[N:11]=[C:8]([C:14]3[CH:13]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH:5]=[CH:6][N:10]=2)=[CH:6][CH:7]=1
Reactant: N=C(N)Cc1ccc(Br)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(Cc2nccc(-c3ccc(Br)cc3)n2)cc1
Yield: 154.7 %

Procedure:
To a stirred mixture of 4-bromophenyl-acetamidine (11.25 g, 0.04 mole) and 1-dimethylamino-3-dimethylimonio-1-(4-bromophenyl)-1-propane perchlorate (15.25 g, 0.04 mole) in 100 mL of dry ethanol is added 0.04 mole sodium ethoxide (prepared from 0.92 g Na and 65 mL ethanol). After stirring for 30 min at room temperature a further equivalent of sodium ethoxide is added, and the mixture is heated under reflux for 2 hr. The solvent is removed under reduced pressure, and the yellow-brown residue triturated with 150 mL water. The solid is filtered, washed with water, dried in air and recrystallized from ether:hexane (1:3) to give 12.5 g (77%) of a pale yellow crystalline solid, mp 93°-94° C.
Reaction SMILES: C(OC([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH2:8][CH2:7]1)=O)C.[CH3:30][Li].C([O:34][CH2:35][CH3:36])C>O1CCCC1>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][CH:6]([C:35]([OH:34])([CH3:36])[CH3:30])[CH2:7][CH2:8]1)=[O:15]
Reactant: CCOC(=O)C1CCC(CNC(=O)c2cccnc2Oc2cccc(Cl)c2)CC1
Reactant: CCOCC
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)C1CCC(CNC(=O)c2cccnc2Oc2cccc(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a 4-({[2-(3-Chloro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid ethyl ester (0.220 grams, 0.53 mmole) in tetrahydrofuran (5 ml) at −78° C. 1.4 M methyl lithium in diethyl ether (1.13 ml, 1.58 mmole) was added dropwise to keep the temperature below −60° C. and stirred at −78° C. for 2 hours and allowed to warm to room temperature. The mixture was quenched with sat'd NH4Cl and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated to a product which was purified by chromatography on silica eluting with 2/3 ethyl acetate/hexane to give an off-white oil. (0.040 g); 1H NMR (400 mhz, CDCl3) d 0.84-1.70 (m, 12H), 1.83-1.87 (m, 4H), 3.30-3.37 (m, 2H), 7.04-7.07 (m, 1H), 7.11-7.19 (m, 2H), 7.24-7.27 (m, 1H), 7.35-7.39 (m, 1H), 7.79 (bs, 1H),8.19-8.21 (m, 1H), 8.60-8.62 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2CCC(NC1C=CC=CC=1C(O)=O)=O.CC1(C)OC(=O)[CH:30]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40](OC)[CH:41]=3)[NH:36][C:35]=2C)C(=O)O1.[C:48]([OH:57])(=O)[C:49]1[C:50](=[CH:52][CH:53]=[CH:54][CH:55]=1)[NH2:51]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:30][CH2:34][C:35]1[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:48](=[O:57])[C:49]3[C:50](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:51]=1)=[CH:6]2
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc2[nH]cc(CCC(=O)Nc3ccccc3C(=O)O)c2c1
Reactant: COc1ccc2[nH]c(C)c(C3C(=O)OC(C)(C)OC3=O)c2c1
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(CCc3nc4ccccc4c(=O)n3-c3ccccc3)cc2c1

Procedure:
The foregoing intermediate product 3-(5-methoxyindol-3-yl)-N-(2-carboxyphenyl)propionamide can be prepared directly from the corresponding Meldrum's Adduct [3-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-methyl-5-methoxyindole] (4.41 g, 14.5 mmol) by reaction with an equivalent amount of anthranilic acid (1.99 g, 14.5 mmol) in 30 ml of pyridine. The reaction is carried out at reflux for two hours after which the pyridine is azeotropically removed under vacuum with toluene [Route B].
Reaction SMILES: [C:1]([N:5]([C:7]([CH3:16])([CH3:15])[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[OH:6])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH:23](Cl)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:16])([CH3:15])[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Reactant: ClC(c1ccccc1)c1ccccc1
Product: CC(C)(C)NC(=O)C(C)(C)N(OC(c1ccccc1)c1ccccc1)C(C)(C)C
Yield: 62.7 %

Procedure:
The compound is prepared in analogy to example A13 from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and diphenylmethylchloride in 62.7% yield as colorless crystals, m.p. 89-92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)#[CH:40]>O1CCCC1.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:40]#[C:39][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in anhydrous tetrahydrofuran (10 mL). Anhydrous triethylamine (20 mL) and a solution of 2-ethynylpyridine (155 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) were added. The solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added. A mixture was stirred at ambient temperature under nitrogen atmosphere overnight; the resulting suspension was filtered through a paddle of silica gel and silica gel was thoroughly washed with ethyl acetate. The obtained filtrate was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified using column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[(pyridin-2-yl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as orange oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]([C:15]([OH:17])=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:18]O>>[Cl-:3].[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH3+:5])[C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H]([NH3+])Cc1ccc(O)cc1
Product: [Cl-]
Reaction time: 24 h
Yield: 84 %

Procedure:
Thionyl chloride (6.62 mmol, 0.48 mL) was added dropwise to a solution of L-tyrosine (0.600 g, 3.31 mmol) in methanol (22 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residual methanol removed by azeotropic distillation with dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (0.646 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[N:15][C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:17][N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:26]([C:30]1[CH:34]=[C:33]([N:35]=[C:36]=[O:37])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:31]=1)([CH3:29])([CH3:28])[CH3:27].CCCCCC>C1COCC1.C(Cl)Cl>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4=[N:18][CH:17]=[C:16]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[N:15]=[C:14]4[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[F:1])=[O:37])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Nc1ccc(Oc2ccnc3nc(N4CCOCC4)cnc23)cc1F
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4nc(N5CCOCC5)cnc34)cc2F)n(-c2ccccc2)n1

Procedure:
A solution of 2-fluoro-4-(3-morpholinopyrido[2,3-b]pyrazin-8-yloxy)aniline (47 mg, 138 mmol) in dry THF (5 mL) was treated with a solution of 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole (1.1 mL of a 0.25 M solution in CH2Cl2, 275 μmol) at 0° C. A yellow precipitate started to form gradually and after 1 h at RT, hexane (20 mL) was added and the yellow precipitate was filtered off. It was redissolved in MeOH/CH2Cl2 (1:1), evaporated onto silica gel and the product was eluted with a gradient of 0% to 20% MeOH in EtOAc to give the product as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:8]=[C:9]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:3]1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[NH:20]1[CH2:21][CH2:22][C@@H:18]([O:17][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[N:8]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: O=c1[nH]nc(-c2cc3ccccc3c(O[C@@H]3CCNC3)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To crude (R)-tert-butyl 3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate was added a minimal amount of NMP and TFA (2 mL). The solution was stirred at RT for 10 minutes and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 15-22% ACN in water (acid mode) to give the title compound (229 mg, 29% over 3 steps).
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH2:26][N:27]2C(=O)C3C(=CC=CC=3)C2=O)([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO>[NH2:27][CH2:26][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:16][CH2:15]1)([C:18]([O:20][CH3:21])=[O:19])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)C(CN)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of 2.9 ml (64 mmol) of hydrazine hydrate in 8 ml of methanol is added to a solution of 27.5 g (58 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl-methyl)malonate in 300 ml of methanol previously cooled to −5° C. The reaction medium is stirred from −5° C. to ambient temperature for 3 h. After evaporation and addition of 300 ml of water, the reaction medium is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated. The residue obtained is purified by chromatography over silica gel eluted with an 8/2 heptane/ethyl acetate mixture then the polarity was increased to a 9/1 ethyl acetate/methanol mixture. 10 g (50%) of dimethyl 2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are thus obtained in the form of a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[C:32]([F:38])[CH:31]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][C:32]=3[F:38])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Reactant: C#Cc1ccc(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4ccc(Cl)cc4F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 47.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 4-chloro-1-ethynyl-2-fluorobenzene (Intermediate-49, 0.022 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.025 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65-0.68 (m, 4H), 1.60 (m, 1H), 4.32 (d, J=6.0 Hz, 2H), 7.33-7.52 (m, 3H), 7.55-7.74 (m, 5H), 7.90 (m, 1H), 8.68 (m, 1H), 12.0 (br s, 1H); MS (m/z): 539.0 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11](CCl)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2.Cl.Cl.[NH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1>>[NH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:16]=[CH:17][CH:18]=[N:19][C:5]=4[N:4]([CH2:3][O:2][CH3:1])[C:9]=3[CH:10]=2)[CH:29]=1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: NCCc1c[nH]cn1
Agent: Cl
Product: COCN1c2cc(-n3cnc(CCN)c3)ccc2Sc2nccnc21
Yield: 116 %

Procedure:
0.5 g of 10-methoxymethyl-8-chloromethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine and 1.0 g of 4-(2-aminoethyl)imidazole dihydorchloride were treated by the same method as the one of Example 1094 to thereby give 0.7 g of crude 8-[4-(2-aminoethyl)imidazol-1-yl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine as a brown solid. This crude product was then treated by the same method as the one of Example 316 to thereby give 0.1 g of N-[2-[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4benzothiazin-8-ylmethyl)imidazol-4-yl]ethyl]methanesulfonamide. Further, it was treated by the same method as the one of Example 8 to thereby give 50 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.CC(C)([O-])C.[K+].[Cl:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=3)[CH:33]=[N:32][CH:31]=2)[CH2:23]1>CS(C)=O>[ClH:20].[ClH:20].[CH3:41][O:40][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][C:36]=1[O:42][CH3:43])[CH:33]=[N:32][CH:31]=[C:30]2[CH2:29][CH2:28][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=3)[C:8]2=[O:13])[CH2:23]1
Reactant: COc1cc2cncc(CCN3CCCC(CCl)C3)c2cc1OC
Reactant: Cc1cc2c(cc1C)C(=O)NCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2cncc(CCN3CCCC(CN4CCc5cc(C)c(C)cc5C4=O)C3)c2cc1OC
Product: Cl

Procedure:
Prepared from 6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline in dimethylsulphoxide with potassium tert.butoxide and 3-chloromethyl-N-[2-(6,7-dimethoxy-isoquinol-4-yl)-ethyl]-piperidine analogously to Example 2.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH:11]=[O:12])[CH2:5][CH2:4]1)[CH3:2].C(C1C=CC(C=O)=CC=1)C>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCC1CCC(CCC=O)CC1
Agent: CCc1ccc(C=O)cc1
Product: CCc1ccc(CCC=O)cc1

Procedure:
4-Ethyl cyclohexanepropanal was similarly prepared as described in Examples I and II. First, 4-ethyl benzaldehyde (925 g, commercially available from Mitsubishi Gas Chemical Company, Inc.) was used to obtain 3-(4-ethyl-phenyl)-propionaldehyde (878 g) with a boiling point of 129° C. at a pressure of 12 mmHg. 3-(4-Ethyl-phenyl)-propionaldehyde (350 g) was consequently used to provide 4-ethyl cyclohexanepropanal (201 g) with a boiling point of 85° C. at a pressure of 3 mmHg.