Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([C:12]#[N:13])[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2c(-c3ccccc3)c(C#N)c(Cl)nc2c1
Reactant: C1CCNCC1
Product: COc1ccc2c(-c3ccccc3)c(C#N)c(N3CCCCC3)nc2c1

Procedure:
The title compound was prepared in analogy to example 27 step C from 2-chloro-7-methoxy-4-phenyl-quinoline-3-carbonitrile and piperidine. Light yellow solid. MS (ESI): 344.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Product: O=C(C=Cc1ccc(F)cc1)C=Cc1ccc(F)cc1

Procedure:
Commercially available 4-fluorobenzaldehyde of formula V-1 is condensed with acetone, under basic conditions, to provide 1,5-Bis-(4-fluorophenyl)-penta-1,4-dien-3-one of formula V-2. The dienone is reduced with magnesium in methanol to provide the ketone of formula V-3. The ketone of formula V-3 is converted to dihydropyrone products of formula V-8 using chemistry analogous to that described in Chart U for the sequence of reactions from U-3 to U-8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Clc1cc(Br)c2ncccc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(Cl)cc2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8-Bromo-6-chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g., 0.025 mole] in 50 ml. of tetrahydrofuran was added dropwise over a 10 minute period to a mixture of butyl lithium (2.3M in hexane, 12.2 ml., 0.028 mole) and 40 ml. of tetrahydrofuran held at -70° C. After an additional 30 minutes at this temperature, a cold (0° C.) solution of diethyl oxalate (14.6 g., 0.10 mole) in 50 ml. of tetrahydrofuran was added dropwise. The reaction mixture was maintained at 0° C. for 1 hour, then quenched at 0°-5° C. with glacial acetic acid (17 ml.) in 50 ml. of tetrahydrofuran. After warming to room temperature the quenched mixture was poured into 500 ml. of water and then diluted with 500 ml. of ethyl acetate and 500 ml. of saturated sodium bicarbonate. The organic layer was separated, washed with 500 ml. of fresh bicarbonate, dried over anhydrous magnesium sulfate, filtered, and evaporated to an oil. Trituration with two 100 ml. portions of hexane gave the title product (2.3 g., m.p. 107°-110° C.; m/e 265/263).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])([O-:3])=[O:2].[OH-].[Na+].Cl>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[C:13]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of Diethyl nitroterephthalate (17.9 g) in 300 mL ethanol was added 1N NaOH (70 mL) and stirred overnight. 1N HCl (70 mL) was added and the reaction was partitioned between methylene chloride (200 mL) and water (200 mL). The aqueous layer was extracted an additional three times. The combined organic extracts were dried and the solvent removed in vacuo to afford Ethyl-3-nitro-4-carboxybenzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.[CH:28]([NH2:31])([CH3:30])[CH3:29].Cl.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:31][CH:28]([CH3:30])[CH3:29]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(CNC(C)C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (3.5 g) and isopropylamine (10 ml) in methanol (125 ml) was stirred at 20° for 1h. The resulting solution was treated with ethanolic hydrogen chloride (0.027 g/ml; 15 ml), cooled to 0° and treated with sodium cyanoborohydride (0.94 g). After stirring for 2.5 h, water (15 ml) was added and the resulting mixture was stirred at 20° for 0.5 h and treated with concentrated hydrochloric acid (6 ml). The mixture was warmed to 40°, stirred at 40° for 0.5h and concentrated in vacuo to ca. 50 ml. The concentrate was then basified (to pH9) with a saturated solution of potassium carbonate (200 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were combined, dried and evaporated to leave a gum (ca. 5 g) which was purified by FCC eluting with System A (100:8:1) to give the title compound (1.9 g) as a solid, m.p. 154°-156°. A second crop of product (0.4 g) has m.p. 150°-154°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>ClCCCl.CC(O)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Fc1ccc(-c2cc3c(Cl)ncnc3s2)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Fc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3s2)cc1
Temperature: 90 °C
Yield: 49.9 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (40 mg, 0.15 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 1 ml) was added 3-chloro-4-fluoroaniline (22 mg, 0.15 mmol). The mixture was heated at 90° C. for 2 days. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (28 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.Cl[C:15]([C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2)=[O:16]>N1C=CC=CC=1>[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15]([C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2)=[O:16]
Reactant: O=C(Cl)C12CCCN1CCC2
Reactant: Nc1cnc2ccccc2c1N
Agent: Cl
Solvent: c1ccncc1
Product: Nc1c(NC(=O)C23CCCN2CCC3)cnc2ccccc12
Yield: 41.8 %

Procedure:
In 330 ml of pyridine was dissolved 5.52 g (34.7 mmol) of 3,4-diaminoquinoline. To the solution was slowly added 7.70 g (36.5 mmol) of 5-chlorocarbonyl-1-azabicyclo[3.3.0]octane hydrochloride while stirring at -15° to 20° C., followed by stirring at 15 to 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and 100 ml of a saturated sodium hydrogen-carbonate aqueous solution was added to the residue. The mixture was extracted with 800 ml of chloroform. The extract was washed with 40.0 ml of a sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by alumina column chromatography to obtain 4.30 g (yield: 41.8%) of the titled compound as an oil. The resulting oil was crystallized from ethanol-diethyl ether to obtain 3.05 g of the titled compound as a pale yellow prism.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]2[C:11]=1[C:10](=[N:15][OH:16])[CH2:9][CH2:8]2
Reactant: NO
Reactant: COc1ccc(C)c2c1C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C)c2c1C(=NO)CC2
Yield: 87.2 %

Procedure:
7-Methoxy-4-Methyl-1-indanon (1.0 g, 0.006 mol) was dissolved in ethanol (10 mL) and hydroxylamine hydrochloride (0.8 g, 0.012 mol) and sodium acetate (0.96 g, 0.012 mmol) were added. The reaction mixture was heated to reflux for 3 h. Then water (10 mL) was added and a precipitation formed which was filtered. The precipitate was washed with water, isolated and dried under high vacuum to yield 7-methoxy-4-methyl-indan-1-one oxime (1.0 g, 92%) as a white solid; MS: m/e=192.4 (M+H+).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([F:44])=[C:18]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:42][CH3:43])=[C:30]([CH2:33][NH:34][C:35]([CH3:41])([C:37]([NH:39][CH3:40])=[O:38])[CH3:36])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1.C=O>C(O)(=O)C.ClCCl>[Cl:15][C:16]1[C:17]([F:44])=[C:18]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:42][CH3:43])=[C:30]([CH2:33][N:34]([CH3:1])[C:35]([CH3:41])([C:37]([NH:39][CH3:40])=[O:38])[CH3:36])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNC(=O)C(C)(C)NCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)C(C)(C)N(C)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Yield: 68.1 %

Procedure:
Solid sodium triacetoxy borohydride (0.2 g, 0.94 mmol) was added to a stirred solution of N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,2-dimethylalaninamide (0.12 g, 0.28 mmol Example 95) in a mixture of acetic acid/dichloromethane (10 ml, 5% v/v) and in the presence of type 4 Å molecular sieves, followed rapidly by aqueous formaldehyde (1 ml). After 10 minutes the reaction mixture was concentrated and purified by preparative LCMS (standard basic system) to give the title product as a white solid, (0.085 g, 69%); 1H NMR Spectrum: (DMSO d6) 1.24 (s, 6H), 2.18 (s, 3H), 2.65 (d, 3H), 3.52 (s, 2H), 3.96 (s, 3H), 7.20 (s, 1H), 7.29 (t, 1H), 7.52-7.62 (m, 2H), 7.79 (m, 1H), 8.44 (m, 2H), 9.78 (s, 1H); Mass Spectrum: (M+H)+ 446.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH3:19])[N:9]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(O)(=O)C.CN(C=O)C>[Br:20][C:11]1[N:10]([CH3:19])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(F)cc2)n1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Temperature: 60 °C
Yield: 35 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (2.7 g, 10.67 mmol) (prepared in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 60° C. overnight. TLC indicated that the reaction was complete. The mixture was quenched slowly with K2CO3 (25 g). When pH was about 5, a precipitate was formed. The precipitate was washed with water (50 mL×5) to give 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (1.24 g, 35%): mp 174.38° C.; Mass spectrum m/z=332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C15H11N3FBr.0.2H2O: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1)[NH2:12]
Reactant: NN
Reactant: Cc1cnc(C)c(Cl)n1
Solvent: O
Solvent: CCO
Product: Cc1cnc(C)c(NN)n1
Temperature: 50 °C
Yield: 27.9 %

Procedure:
A reaction flask was loaded with 2-chloro-3,6-dimethylpyrazine (10 g) and ethanol (15 ml), and heated up to 50° C. with stirring. To this, a mixture of hydrazine monohydrate (11.2 g) and ethanol (10 ml) was dropwise added in one hour. The temperature was raised to the reflux temperature, followed by stirring for six hours. The heating was stopped and the reaction mixture was condensed by an evaporator. The precipitated crystals were filtrated for collection and dried to give 2-hydrazino-3,6-dimethylpyrazine (2.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)nc1
Product: O=Cc1ccc(Oc2ccc(Cl)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 6-chloropyridin-3-ol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:21]>CO>[CH2:1]([O:8][CH2:9][C:10]([NH2:21])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)C=C(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 14.48 g (0.6129 mol) of ethyl 4-benzyloxy-3-oxo-butanoate in 145 ml of methanol, 20.54 g (0.3258 mol) of ammonium formate was added, and the resulting mixture was heated under reflux for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was evaporated off under reduced pressure. To the reside, 100 ml of ethyl acetate and 100 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, washed twice with each 50 ml of a brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective ethyl 4-benzyloxy-3-amino-2-butenoate (7.61 g, colorless liquid). The yield was 52.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][CH2:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41](I)[CH:42]=[CH2:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)[CH2:16][C@H:15]([CH2:43][CH:42]=[CH2:41])[C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:29][CH:30]=1
Reactant: C=CCI
Reactant: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
A solution of (R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (67 mg, 0.155 mmol) in THF (1 mL) is cooled to 0° C., then LiHMDS (0.31 mL, 1.0 M in THF, 0.31 mmol) is added. After addition, the resulting solution is further stirred at 0° C. for 45 min. Then allyl iodide (52 mg, 0.31 mmol) is added at 0° C. The resulting mixture is stirred at 0° C. for 1 h and 45 min, then the reaction is quenched with saturated NH4Cl solution (0.2 mL). THF is removed by evaporation and then the residue is dissolved in CH2Cl2 (40 mL), washed with brine (10 mL) and dried over Na2SO4. After concentration, the residue is purified on silica gel (0-50% ethyl acetate in hexane) to give (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (58.5 mg, 80%) and its (3R)-diastereomer (6.5 mg, 9%) as a colorless oil. HPLC-MS calculated for C26H21ClF3NO2 (M+H+) 472.12, found 472.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Product: C=CCN1CCN(c2cc(Cl)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and allylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV)) 305 (M+, 7), 96 (57), 69 (bp), 68 (48), 56 (69).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]([OH:28])[CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[NH:36][C:37](=O)[O:38]C1C=CC=CC=1.O.C(OCC)(=O)C.O1CCCC1>CS(C)=O>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][C@H:21]([OH:28])[CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:32]2[S:31][CH:35]=[CH:34][N:33]=2)=[O:38])=[CH:30][CH:29]=1)#[N:18]
Reactant: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)cc3)c2cc1C#N
Temperature: 85 °C
Yield: 54.5 %

Procedure:
After dissolving 4-(4-aminophenoxy)-6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline (105 mg, 0.2583 mmol) in dimethylsulfoxide (1 ml), there was added phenyl (thiazol-2-yl)carbamate (60 mg, 0.2712 mmol), and the mixture was heated and stirred at 85° C. for40minutes. After cooling to room temperature, water was added to the reaction solution, extraction was performed with ethyl acetate-tetrahydrofuran, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. Upon distilling off the solvent, the residue was dissolved in acetone and diluted with diethyl ether, and the precipitate was washed with diethyl ether and blow-dried to obtain the title compound (75 mg, 0.1408 mmol, 54.51%) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35].Cl>ClCCl>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([NH:1][S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
To a mixture of [4-(6-amino pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.10 g, 0.285 mmol) and triethyl amine (0.037 g, 0.371 mmol) in 10 mL of dichloromethane at 0° C. was added n-propylsulphonyl chloride (0.044 g, 0.313 mmol). The reaction mixture was stirred at room temperature for 4 hours and then dilute hydrochloric acid solution was added (20 mL). The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, the concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (46.3 mg, 35.5% yield). 1H NMR (400 MHz, CDCl3) δ 7.75, 7.63-7.66, 7.56-7.59, 7.37, 7.25, 6.99, 4.04-4.07, 3.85-3.89, 3.71-3.78, 3.35, 1.96-2.00, 1.1.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][C:12]=2[N+:21]([O-])=O)[O:6][CH2:5][CH2:4][O:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][C:12]=2[NH2:21])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(CCCNc2c([N+](=O)[O-])cnc3ccccc23)OCCO1
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CC1(CCCNc2c(N)cnc3ccccc23)OCCO1
Yield: 97.3 %

Procedure:
The product from the previous step, [3-(2-methyl-[1,3]dioxolan-2-yl)propyl](3-nitro-quinolin-4-yl)amine (29.5 g, 93.0 mmol), was stirred with sodium dithionite (67.0 g, approximately 85% pure), potassium carbonate (51.4 g, 372 mmol), and ethyl viologen dibromide (0.37 g, 1 mmol) in a mixture of dichloromethane and water (375 mL each) for 15 hours. The layers were then separated, and the organic phase was washed successively with a saturated aqueous sodium bicarbonate solution and water (250 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N4-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]quinoline-3,4-diamine (26.0 g) as a dark solid that was used directly in the next step without further purification.
Reaction SMILES: O([CH2:8][CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[CH:11]1)C1C=CC=CC=1.[CH3:22][O:23][C:24]([O:31][CH3:32])([O:29][CH3:30])[CH2:25]CCBr>>[CH3:22][O:23][C:24]([O:31][CH3:32])([O:29][CH3:30])[CH2:25][CH2:8][CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[CH:11]1
Reactant: COC(CCCBr)(OC)OC
Reactant: O=C(O)c1cccc2c1ccn2CCOc1ccccc1
Product: COC(CCCn1ccc2c(C(=O)O)cccc21)(OC)OC

Procedure:
This compound is prepared analogously to Intermediate AO 1-(2-Phenoxy-ethyl)-1H-indole-4-carboxylic acid replacing (2-bromoethoxy)benzene with trimethyl 4-bromoorthobutyrate.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33].OS(O)(=O)=O.Cl.C([BH3-])#N.[Na+].C(=O)C1C=CC=CC=1>O.CO.CO.C(Cl)(Cl)Cl>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@@H:10]2[OH:19])[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Solvent: O=Cc1ccccc1
Solvent: CO
Solvent: O
Product: NC[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C

Procedure:
Kanamycin A sulphate (24.3 g., 0.03 mole) was dissolved in water (150 ml.) and the pH adjusted to 6 by the dropwise addition of 5N hydrochloric acid. Sodium cyanoborohydride (1.95 g., 0.03 mole) was added and the mixture was cooled to 0° C. and stirred while a solution of benzaldehyde (3.61 g., 0.033 mole) dissolved in methanol (15 ml.) was added slowly over the course of 2 1/2 hours. The mixture was allowed to warm to room temperature. After 16 hours the pH of the solution was adjusted to 5.5 by the addition of 1N hydrochloric acid and the solution was filtered and added to a column of Amberlite CG-50 ion-exchange resin in the ammonium-ion form. Elution first with water and then with a gradient of ammonium hydroxide of increasing concentration from 0-0.7N gave as major product 3-N-benzylkanamycin A contaminated with some 1-N-benzyl derivative (5.0 g., 28%) Rf 0.44 in methanol-chloroform-17% ammonium hydroxide 4:1:2. (Kanamycin A gave an Rf value of 0.15).