Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13]([CH:15]([OH:21])[C:16](=[NH:20])[O:17]CC)[CH:14]=1.[O:25]1CCC[CH2:26]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13]([CH:15]2[O:21][C:26](=[O:25])[NH:17][C:16]2=[O:20])[CH:14]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1cc(Cl)ccc1OCC
Agent: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1ccc(Cl)cc1C1OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
By the procedure of Example 54, but using only 2.3 equivalents of triethylamine, ethyl 1-(5-chloro-2-ethoxyphenyl)-1-hydroxymethanecarboximidate (8.0 g., 0.029 mole) in 300 ml. of tetrahydrofuran was reacted with phosgene. After stirring for 2 hours at room temperature, isolation was also according to Example 54, substituting chloroform for ethyl acetate, resulting in toluene recrystallized 5-(5-chloro-2-ethoxyphenyl)-oxazolidine-2,4-dione (2.7 g., m.p. 197°-199° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][N:11]3[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:4][CH:3]=1.[NH:27]([CH2:29]C(O)=O)[CH3:28].[CH2:33]=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]4[O:17][CH2:33][N:27]([CH3:29])[CH2:28]4)[CH:13]=[CH:12][N:11]3[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C=O)ccn23)n1
Reactant: C=O
Reactant: CNCC(=O)O
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C4CN(C)CO4)ccn23)n1

Procedure:
A 250 mL round bottom flask equipped with a Dean Stark trap was charged with aldehyde 40 (1.44 g, 3.95 mmol), toluene (120 mL), sarcosine (710 mg, 7.97 mmol), and paraformaldehyde (600 mg, 20.0 mmol), and the reaction was heated under reflux for 12 hours, then concentrated under reduced pressure, dissolved in a minimum volume of acetone, and filtered through a 5 g silica cartridge, which was then washed with 80 mL of acetone. The filtrate was then concentrated under reduced pressure, and not purified further. Yield of 41: 1.65 g (98%). 1H NMR (400 MHz, CDCl3) δ 2.63 (bs, 6H), 2.94 (m, 1H), 3.55 (m, 1H), 4.65 (m, 1H), 4.69 (m, 1H), 5.18 (m, 1H), 6.80 (d, J=5.4 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 7.13 (t, J=8.4 Hz, 2H), 7.61 (m, 2H), 7.69 (s, 1H), 8.29 (d, J=5.4 Hz, 1H), 9.56 (d, J=7.6 Hz, 1H). MS (ESI+) 410.2 (under MS conditions, the aminal bond is cleaved and instead an M+1 peak is observed for the resulting 7-C(OH)HCH2N(Me)H product).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:2](=[O:3])[O:4][CH3:5])=[CH:19][CH:18]=2)[N:13]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(-c2noc(-c3ccccn3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(-c2noc(-c3ccccn3)n2)cc1

Procedure:
1.4 g. (0.015 mole) of methyl chloroformate is added to a mixture of 2.4 g. (0.01 mole) of 5-(2-pyridyl)-3-(4-aminophenyl)-1,2,4-oxadiazole, from part (b), and 2.1 g. of potassium carbonate in 50 cc. of dioxane. The resulting mixture is refluxed for 0.5 hours. It is then concentrated to dryness and the residue is crystallized from benzeneethyl acetate to yield [4-[5-(2-pyridyl)-1,2,4-oxadiazol-3-yl]-phenyl]carbamic acid, methyl ester.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1cnc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 254.7 %

Procedure:
To a solution of 4-(trifluoromethyl)-1H-imidazole (10.0 g, 73.5 mmol) in THF (75 mL) at 0° C. was added sodium hydride (60% in mineral oil, 3.25 g, 80.8 mmol) under nitrogen. The mixture was stirred at 0° C. for 30 min. Methyl bromoacetate (1.67 mL, 17.6 mmol) was added and the reaction was stirred for 3 h at room temperature. LC-MS showed the reaction was complete. The solvent was removed under reduced pressure. The crude material was redissolved in diethyl ether and washed with sat. aq. ammonium chloride and 1N HCl aqueous solution. The combined aqueous layer was reextracted with ethyl acetate three times. The combined organic layer was dried over MgSO4, filtered, and evaporated to a mixture of solid and oil. The crude was filtered to remove most of the oil, and the solid was washed with heptane. This yellow solid was triturated in a minimum amount of diethyl ether to wash off the yellow impurities. The material was filtered and the solid was retriturated with diethyl ether again. The filtrate was concentrated and the previous trituration steps were repeated. This afforded (I-36a) as a white solid (9.33 g, 61%); 1H NMR (400 MHz, CDCl3): δ 7.53 (1 H), 7.30 (1 H), 4.73 (2 H), 3.81 (3 H); m/z 209.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][C:42]=1[OH:56].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:56][C:42]1[CH:43]=[CH:44][C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:46][C:41]=1[O:40][CH3:39]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)ccc1O
Yield: 76 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 63 mg (68% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([Cl:12])[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:5]2=[C:9]([Cl:12])[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(Cl)ccn2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a stirred solution of 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine (0.530 g, 2.38 mmol) in CH2Cl2 (20 mL) was added DIPEA (0.832 mL, 4.76 mmol) and pyridin-2-ylmethanamine (0.283 g, 2.62 mmol) and the contents were stirred for 10 min at room temperature. The reaction mixture was washed with water and the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a brown solid. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 20% EtOAc/hexanes) to give 2,5-dichloro-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.400 g, 57.0%) as an off-white solid. LCMS Condition B-12: retention time 2.20, [M+1]=294.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.87 (d, J=5.7 Hz, 2H), 6.81 (d, J=2.8 Hz, 1H), 7.32 (t, J=1.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.81 (d, J=2.8 Hz, 1H), 7.83 (t, J=1.6 Hz, 1H), 8.48 (t, J=5.2 Hz, 1H), 8.57 (d, J=1.2 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:7][N:6]2[CH:8]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Reactant: c1cc[nH]c1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(-n3cccc3)ccc2n1
Yield: 7 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (80 mg, 0.2 mmol) was converted, using pyrrole instead of benzamide, to the title compound (5 mg, 7%) which was obtained as a light yellow solid. MS: m/e=341.3 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl.C(OCC)(=O)C>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 4,4-difluoropiperidin hydrochloride (2.15 g, 14 mmol) in 30 mL of dichloromethane was added triethylamine (5.7 ml, 41 mmol), followed by 4-nitrophenyl chloroformate 40 (3.0 g, 15 mmol). After 1 h, the reaction was diluted with ethyl acetate and was washed with 3×30 mL of sat. NaHCO3, and 1×30 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate 41 (3.9 g, 100% yield). 1H-NMR (400 MHz, CDCl3): δ 8.26 (m, 2H), 7.30 (m, 2H), 3.76 (m, 4H), 2.09 (m, 4H). MS 286.1 (calc'd) 287.1 (M+H, found).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=2.[CH3:14][S:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.Cl[Sn](Cl)(Cl)Cl.[N+]([CH3:33])([O-])=O>>[CH3:33][C:5]1[S:1][C:2]2[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][C:3]=2[C:4]=1[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([S:15][CH3:14])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1=CCc2ccsc21
Reactant: C[N+](=O)[O-]
Reactant: CSc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)C1CCc2c1sc(C)c2C(=O)c1ccc(SC)cc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A 14.25 g (0.068 moles) sample of ethyl 4H-cyclopenta[b]thiophene-6-carboxylate, the product of Example 1g., and 13.92 g p-(methylthio)benzoyl chloride were dissolved in 410 ml of dry nitromethane and placed under argon and cooled to -20° C. An 8 ml sample of SnCl4 was added dropwise controlling the temperature at -20° C. After the addition was complete the reaction mixture was stirred at -20° C. for 15 min. after which it was allowed to warm slowly to room temperature and stirred for 30 min. The reaction was poured into ice water and extracted three times with Et2O. The organics were combined, washed with 3-dimethylaminopropylamine solution, 3N hydrochloric acid, water, brine, and dried (MgSO4). Evaporation of the solvent gave a dark green oil which was flash chromatographed on silica gel using 1:20 EtOAc:hexane as the eluant. The resulting solid was recrystallized from methylcyclohexane/EtOAC to give 15.32 g of ethyl 5,6-dihydro-2-methyl-3-[4-(methylthio)benzoyl]-4H-cyclopenta[b]thiophene-6-carboxylate, mp 62-64° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C@H:6]([NH:22][C:23](=O)[O:24]C(C)(C)C)[C@H:7]([OH:21])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1.[CH3:34]CN(CC)CC.C(C1NC=CN=1)(=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:24])[CH3:34])[C@H:7]([OH:21])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Reactant: CCN(CC)CC
Agent: CC(=O)c1ncc[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-3,4-dihydro-2H-chromen-4-yl)amino]propylcarbamate (3.0 g, 5.2 mmol) was dissolved in 30 mL of 25% TFA/CH2Cl2 and stirred at room temperature for 30 min. The mixture was diluted with CH2Cl2 50 mL and washed with NaHCO3 (2×30 mL). The organic layer was washed with brine (1×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the resulting residue dissolved in 52 mL of CH2Cl2. The mixture was chilled to 0° C. followed by the addition of Et3N (1.0 mL, 11.9 mmol) and acetyl imidazole (0.68 g, 6.2 mmol). The mixture was warm spontaneously over night. The CH2Cl2 was removed in vacuo and the residue dissolved in EtOAc (100 mL) and washed with 1N HCl (2×30 mL), NaHCO3 (1×30 mL), brine, dried over Na2SO4, and conc. in vacuo to yield 2.5 g (92%) of the title compound as a light yellow solid. MS (ESI+) for C21H23F2IN2O3 m/z 517.0 (M+H)+.
Reaction SMILES: CSC1SC(C(OC)=O)=CC=1N[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]([O:34][CH3:35])=[S:33])[S:29][C:30]=1[CH3:31].C1(C2C=CC(B(O)O)=CC=2)C=CC=CC=1>>[C:16]1([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]3[CH:27]=[C:28]([C:32]([O:34][CH3:35])=[S:33])[S:29][C:30]=3[CH3:31])=[CH:23][CH:24]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(Nc2ccc(-c3ccccc3)cc2)c(SC)s1
Reactant: COC(=S)c1cc(N)c(C)s1
Agent: OB(O)c1ccc(-c2ccccc2)cc1
Product: COC(=S)c1cc(Nc2ccc(-c3ccccc3)cc2)c(C)s1
Yield: 19.1 %

Procedure:
Methyl 5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 142.5 mg (2 equiv, 0.72 mmol) of 4-phenylphenyl boronic acid to give 24.5 mg (19.1%) of methyl 4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H), 7.08-7.14 (m, 2H), 7.33 (m, 1H), 7.43-7.46 (m, 2H), 7.54-7.60 (m, 411), 7.82 (s, 1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)[CH3:14])[CH3:10].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(O)=O>C1COCC1.CCOCC>[CH2:9]([O:11][C:12](=[O:26])[C:13]([CH3:14])([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)[CH:39]([C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:42][CH:41]=1)[OH:40])[CH3:10]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)Oc1ccc2ncccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(Oc1ccc2ncccc2c1)C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.05 h
Yield: 86 %

Procedure:
To a LDA solution (42 mL, 1.5 M solution in THF) in 65 mL of dry THF at −78° C., a solution of 2-(quinolin-6-yloxy)-propionic acid ethyl ester (8.61 g, 0.035 mol) in 65 mL of dry THF was cannulated in. The resulting solution is allowed to stand at −78° C. for 3 min. Solid 4-benzyloxy-benzaldehyde (6.71 g, 0.032 mol) was added and resulting mixture was allowed to stand at −78° C. for 5 min until all solid dissovled in the solution. Reaction was then quenched with AcOH (6.03 mL, 0.105 mol) in 60 mL of THF at −78° C. The mixture was then diluted with Et2O and washed with sat'NH4Cl, water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography to give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester in 86% yield. A of solution of 2.75 g of give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (6.01 mmol), trifluoroacetic acid (2.8 mL, 36.1 mmol), triethylsilane (5.8 mL, 36.1 mmol) in 80 mL of dichloroethane was heated to reflux for 50 h. The mixture was cooled to r.t. and diluted with Et2O and washed with sat' NaHCO3, water and brine. Organic layer was dried over Mg SO4, filtered and concentrated. Residue was purified by chromatography (5% MeOH in CH2Cl2) to give 86% of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ8.78 (dd, 1H, J=4.4, 1.6 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.98 (d, 1H, J=8.8 Hz), 7.45-7.32 (m, 7H), 7.19 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 6.93 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.23 (q, 2H, J=7.1 Hz), 3.38, 3.18 (ABq, 2H, J=13.8 Hz), 1.53 (s, 3H), 1.19 (t, 3H, J=7.1 Hz). MS (ES+) m/z mass calcd for C28H28O4 (m+1) 442, found 442.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH3:7][N:8]([CH3:31])[NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:29][C:27]([F:28])([F:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:15]1[NH:16][C:17](=[O:20])[C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N:9]([CH3:3])[N:8]([CH3:31])[CH3:7])[CH:19]=2
Reactant: CN(C)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)N(C)c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
0.1 ml of acetic acid, 26.2 μl of a 37% formalin aqueous solution, and 25.3 mg (0.403 mmol) of sodium cyanoborohydride were added to 1 ml of a methanol solution containing 28 mg of the 7-(2,2-dimethylhydrazino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 149. The obtained mixture was stirred at a room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution. The mixture was extracted with ethyl acetate, and was then dried over anhydrous sodium sulfate. The extract was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 2:1), so as to obtain 25.5 mg (88%) of 3-(2-trifluoromethylphenyl)-7-(1,2,2-trimethylhydrazino)-2H-isoquinolin-1-one in the form of a light yellow solid.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[NH:9])[O:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH2:21]([O:20][C:18]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][CH:3]([CH3:10])[CH3:2])=[O:19])[CH3:22]
Reactant: CCOC(=N)CC(C)C
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N=C(CC(C)C)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
Ethyl 3-methylbutanimidate hydrochloride (4.0 g, 24.2 mmol) was suspended in DCM (48 mL) and the mixture was cooled to 0° C. Pyridine (10.0 mL, 124 mmol) was added and the mixture was stirred for 15 minutes. Ethyl chloroformate (5.3 mL, 48.3 mmol) was added and the solution was allowed to warm to RT and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1:1, 200 mL) and solids were removed by filtration through a diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-3-methyl-butanimidate (4.3 g, 88%) as a colorless viscous oil. 1H NMR (400 MHz, DMSO-d6): δ 4.09 (q, J=7.1 Hz, 2H), 4.05 (q, J=7.1 Hz, 2H), 2.18 (d, J=7.4 Hz, 2H), 1.95-1.94 (m, 1H), 1.20 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H), 0.86 (d, J=6.7 Hz, 6H).
Reaction SMILES: [Br:1][CH:2]([C:4]1([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[C:18]=3Br)[CH:13]=2)[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)[CH3:3].[N+](C1C=CC=CC=1)([O-])=O.Br.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][CH:2]([C:4]1([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[CH:13]=2)[O:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9]1)[CH3:3]
Reactant: COc1ccc2cc(C3(C(C)Br)OCC(C)(C)CO3)ccc2c1Br
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C3(C(C)Br)OCC(C)(C)CO3)ccc2c1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-5,5-dimethyl-1,3-dioxane (9.16 g, 10 mmol) is dissolved in toluene (40 ml) and nitrobenzene (2 g) saturated with HBr at room temperature. Phenol (11.28 g, 120 mmol) is added as solid; the mixture is stirred for 2.5 hours, then is poured in 30 minutes under stirring into a 10% aqueous sodium carbonate solution (150 ml), the organic layer is separated and the aqueous phase is extracted with toluene. The combined organic extracts are washed with water, dried on sodium sulphate and the solvent is removed in vacuo. 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-5,5-dimethyl-1,3-dioxane is obtained (75% yield).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26](O)=[O:27].[C:29]([C:33]1[CH:38]=[C:37]([CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:36]=[C:35]([NH2:46])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:29]([C:33]1[CH:38]=[C:37]([CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:36]=[C:35]([NH:46][C:26](=[O:27])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(N)nc(CN2CCOCC2)c1
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CN2CCOCC2)nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64 %

Procedure:
Dissolve [2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid dihydrochloride (6.24 g, 14.84 mmol) and 4-tert-butyl-6-morpholin-4-ylmethyl-pyridin-2-ylamine (3.70 g, 14.84 mmol) in anhydrous DMF (40 mL). Add diisopropyl-ethylamine (8.5 mL, 48.97 mmol) and HATU (6.21 g, 16.32 mmol). Stir the reaction mixture at room temperature for 40 minutes. Dilute with ethyl acetate (800 mL). Wash with aqueous saturated sodium chloride (3×100 mL), sodium bicarbonate (sat. 3×100 mL), water (3×100 mL). Dry the organic layer over magnesium sulfate, filter off the drying reagent, and concentrate to oil. Chromatograph the crude product on silica (0-4% 2 M ammonia methanol/dichloro-methane). Recrystallize from dichloromethane/ether/hexane to provide the title compound 5.50 g (9.5 mmol, 64%) white solid as product. MS (ES), m/z 579 (M+1).