Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.[H-].[Na+]>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (3.59 g, 24.39 mmol) and 2,6-dichlorobenzyl bromide (7.05 g, 29.39 mmol) in dimethylformamide (20 mL) at 0° C. was added 60% sodium hydride (1.176 g, 29.39 mmol). After stirring at ambient temperature for 16 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium chloride and dried (MgSO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded the title compound as an off-white solid (7.38 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[CH2:19]([C:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[O:23][N:22]=1)C>>[CH3:19][C:21]1[CH:25]=[C:24]([C:26]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:10][CH:11]=2)=[O:27])[O:23][N:22]=1
Reactant: CCc1cc(C(=O)O)on1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Product: Cc1cc(C(=O)NCCCCc2ccc(-c3ccc(=O)[nH]n3)cc2)on1

Procedure:
By treating 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one and 3-ethyl-5-carboxyisoxazole in the same manner as in Example 87, 6-{4-[4-(3-methylisoxazole-5-ylcarbonylamino) butyl]phenyl}pyridazin-3(2H)-one was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(c2cccnc2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine with TBTU and DIPEA in THF.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([NH:17][C:18](=[O:27])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:4]=2)=[CH:30][CH:31]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2N)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C(C)=O)cc3)ccc2N)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
In a pressure vessel, N-[2-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxybenzamide (116) (170 mg, 0.462 mmol), 1-(4-bromophenyl)ethanone (184 mg, 0.923 mmol), (or any aryl bromide from the tables below), DME (4.6 mL per mmol of 116) and H2O (2.15 mL per mmol of 116) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen. Pd(PPh3)4 (27 mg, 0.023 mmol, 0.05 eq.) and Na2CO3 (147 mg, 1.38 mmol, 3.0 eq.) were then added and oxygen was removed after each addition. The pressure vessel was sealed and the mixture was stirred at 75° C. overnight. The mixture was cooled at room temp., water was added and the mixture was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over MgSO4 and concentrated to give 42 mg (25%) of the title compound 117. 1H NMR (DMSO-d6) (ppm): 9.61 (s, 1H), 7.96 (dd, J=12.8, 8.8 Hz, 4H), 7.70 (d, J=8.8 Hz, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.42 (dd, J=8.4, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H), 2.58 (s, 3H). MS (m/z): 360.41 (calc) 361.1 (MH+) (found).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)[C:11]#N)=[CH:6][CH:5]=1)[CH3:2].O=[CH:25][C:26](=C)[CH3:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=3)[CH:25]=[C:26]([CH3:27])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=C(C)C=O
Reactant: CCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: CCOc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-ethoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a brown powder (yield 3%), melting at 135-139° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:20])[C:11]([C:21]([OH:23])=[O:22])=[CH:10]2)=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+]>CS(C)=O>[F:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[N:6]=[N:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=1)[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]2=[O:20]
Reactant: C[S-]
Reactant: O=C(O)c1cn(Cc2ccc(Cl)nn2)c2c(F)cccc2c1=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccc(Cn2cc(C(=O)O)c(=O)c3cccc(F)c32)nn1

Procedure:
To a solution of 1-[(6-chloropyridazin-3-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.050 g, 0.15 mmol) in 1 mL of DMSO was added sodium thiomethoxide (0.032 g, 45 mmol). The reaction mixture was irradiated in the microwave at 100° C. for 10 minutes, and purified via reverse phase HPLC to provide 8-fluoro-1-{[6-(methylthio)pyridazin-3-yl]methyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 346.1 for M+H+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2ncccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ccc2ncccc2n1

Procedure:
The title compound (0.48 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.59 g) and 2-chloro-1,5-naphthyridine Rapoport, et al J. Org. Chem. (1971), 36(3), 450-4 (0.40 g) according to the method of D30.
Reaction SMILES: [Li].[OH-].O.[O:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([CH2:20][C:21](OC)=[O:22])=[CH:19][C:6]1=2>O1CCCC1>[OH:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][OH:22])=[CH:19][C:6]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Li]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
In this process, 20 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate is dissolved in 500 ml of tetrahydrofuran. To the solution is added 6.0 g of lithium alminium hydroxide and the mixture is stirred at room temperature for one hour. After decomposing an excess of the reagent by the addition of water to the solution, the mixture is filtered to remove an inorganic salts and the filtrate is concentrated to dryness under reduced pressure to obtain 17.7 g of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: O=Cc1cc(F)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)c(C2OCCO2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of 2.0 g (9.9 mmol) 2-bromo-5-fluorobenzaldehyde in 20 ml toluene were added 0.722 ml (13.0 mmol) ethane-1,2-diol and 5 mg (0.03 mmol) toluene-4-sulfonic acid monohydrate. The reaction mixture was heated in a rotary evaporator at 60° C. and 200 mbar during 4 h. After evaporation of the solvent and flash chromatography 2.32 g (95%) of the title compound were obtained as a colorless liquid.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21](=[CH2:1])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(=O)c1c(OC)cccc1OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (61.1 g, 1.2 equiv) in THF (350 ml) at 0 C was added potassium bis(trimethylsilyl)amide (260 ml of a 15% solution in toluene, 1.2 equiv) and this mixture was stirred at 0 C for 15 min and at r.t. for 45 min. Then, a solution of the ketoester 16 (33.7 g, 141 mmol) in THF (70 ml) was added at 0 C and stirring was continued at r.t. for 1 h. The reaction was quenched by addition of a saturated solution of NH4Cl and ice. The product was extracted into i-PrOAc and the organics were dried over Na2SO4 and filtered through small pad of silica. Purification of the residue by filtration through a plug of silica (1.5 L) with EtOAc/hexane 10 and 15% yielded 26.92 g (81%) of 17 as a colorless oil.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CC(C)([O-])C.[K+].[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>C1COCC1>[CH:15]1([C:18]2[O:19][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:17][CH2:16]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(Cl)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1C1CC1

Procedure:
A mixture of ethyl isocyanoacetate (13.4 g) in THF (65 ml) was added dropwise to a stirred solution of potassium tert-butoxide (14.5 g) in THF (97 ml) at 0° C. Cyclopropanecarboxylic acid chloride (5.4 ml) was added dropwise at below 10° C. and the solvent evaporated. Water (68 ml) and acetic acid (3.4 ml) was added to the mixture, then diisopropyl ether (2×150 ml) was added and the layers separated. The aqueous layer was further extracted with diisopropyl ether (2×150 ml) and the combined organic extracts were dried. Evaporation of the solvent afforded the title compound as a yellow oil (8.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([Cl:21])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Cl
Temperature: 40 °C
Yield: 41.6 %

Procedure:
6-(4-Fluorophenyl)-2-methyl-3-pyridinecarboxylic acid (0.2 g, 0.866 mol) was suspended in DCM (14 mL) and DMF (1 drop) was added. The mixture was cooled in an ice-bath and oxalyl chloride (0.226 mL, 2.598 mmol) was added portion wise over 5 minutes. The mixture was heated to 40° C. for 90 minutes. The mixture was allowed to cool and the solvent removed under vacuum to give 6-(4-fluorophenyl)-2-methyl-3-pyridinecarbonyl chloride as a yellow solid (0.270 g) which was used directly in step 2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[NH2:6][C:4]([C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cccc(N)c1C(N)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1cccc(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 2-amino-6-methylbenzamide (1.28 g, 8.52 mmol) and triethylamine (1.03 g, 10.2 mmol) in THF (30 mL) was added dropwise ethyl chloroglyoxylate (1.28 g, 9.38 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether-ethanol, and the insoluble material was collected by filtration to give ethyl ((2-(aminocarbonyl)-3-methylphenyl)amino)(oxo)acetate as a white powder (1.85 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1ccccc1Br

Procedure:
Prepared by Procedure U and Scheme AK using 2-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [BrH:1].[CH:2]1([C:5](O)([CH2:7][CH2:8][O:9][CH:10]([CH3:12])[CH3:11])[CH3:6])[CH2:4][CH2:3]1>>[Br:1][CH2:4][CH2:3][CH:2]=[C:5]([CH3:6])[CH2:7][CH2:8][O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)OCCC(C)(O)C1CC1
Reactant: Br
Product: CC(=CCCBr)CCOC(C)C
Reaction time: 0.5 h

Procedure:
19 cc of 48 % hydrobromic acid are added dropwise, whilst stirring, at 0°C, over the course of 15 minutes, to 27.7 g of crude 2-cyclopropyl-4-isopropoxy-2-butanol. The mixture is stirred at 0°-5°C over the source of 30 minutes, and subsequently extracted with ether. The ether extract is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue (20.2 g) is chromatographed with hexane/ethyl acetate (98:2) and (95:5) on silica gel. A chromatographically pure cis, trans isomeric mixture of 1-bromo-6-isopropoxy-4-methyl-3-hexene is obtained, nD20 = 1.4802.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29](OC)([O:31]C)[CH3:30]>CN(C=O)C>[CH3:24][N:12]([CH2:13][C:14]1[N:15]([CH3:23])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([NH:1][CH2:28][C:29](=[O:31])[CH3:30])=[CH:3][CH:4]=1
Reactant: COC(C)(CBr)OC
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 18 h
Yield: 9.6 %

Procedure:
To a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.12 g, 0.32 mmol), from Example 1, in DMF (1 mL) was added NaH (14 mg, 60% dispersion in oil, 0.35 mmol) and 1-bromo-2,2-dimethoxy-propane (0.05 mL, 0.37 mmol). After 18 h at RT, the reaction was complete by TLC analysis. The solvent was removed under vacuum and the residue was purified by reverse phase preparative HPLC (YMC CombiPrep® ODS-A, 10% to 90% CH3CN/H2O+0.1% TFA) to give the title compound (11.6 mg) as a pale yellow oil: 1H NMR (400 MHz, MeOH-d4, 2:1 mixture of rotamers, minor rotamer in italics) δ 9.28 and 9.22 (s, 1H), 8.60 and 8.52 (s, 1H), 8.25 and 8.15 (d, 1H), 7.68 (d, J=16 Hz, 1H), 7.50 (m, 1H), 7.35 (m, 3H), 7.15 (m, 1H), 7.02 (m, 1H), 6.55 and 6.25 (s, 1H), 5.05 and 4.95 (s, 2H), 3.72 and 3.68 (s, 3H), 3.50 and 3.48 (s, 3H), 3.35 (s, 2H), 3.15 and 3.10 (s, 3H). MS (ES+) m/e 376.3 (M+H)+. Unreacted (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (68 mg) was also recovered.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[NH:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>>[ClH:2].[ClH:1].[ClH:2].[N:24]1([CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:18]([CH:19]=2)=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)[CH:10]=3)[CH:28]=[CH:27][CH:26]=[CH:25]1
Reactant: c1cc[nH]c1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: c1ccn(CCOc2ccc3cc4ccc(OCCn5cccc5)cc4nc3c2)c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and pyrrole as described in Example 46.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CN(C2CNC2)CCO1
Product: O=C1N=C(N2CC(N3CCOCC3)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Azetidin-3-yl-morpholine following General Procedure C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:28]=[N+:29]=[N-:30].[Na+]>>[C:22]1([C:20]2[CH:19]=[CH:18][C:16]3[CH2:17][CH:13]([CH2:12][N:28]=[N+:29]=[N-:30])[O:14][C:15]=3[CH:21]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(-c4ccccc4)cc3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2ccc(-c3ccccc3)cc2O1

Procedure:
Treatment of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.280 g, 0.736 mmol) with sodium azide (0.191 g, 2.94 mmol) generally according to the procedure described for Intermediate 98 gave (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.026 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.190 g (90%) of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a tan solid, hydrobromide salt. mp 218-221° C. Anal. calcd. for C15H15NOHBr: C, 58.84; H, 5.27; N, 4.57. Found: C, 54.80; H, 4.88; N, 4.18.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:26]([C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)(=[O:28])=[O:27])[CH:21]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:35]([N:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:24][CH2:23]2)[S:26]([C:29]1[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=1)(=[O:28])=[O:27])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a cooled stirred solution of 6-[Benzyl-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (391 mg, 0.80 mmol) in dichloromethane (20 ml). The mixture was allowed to warm to room temperature and stirred for 3 hrs then cooled and quenched with 2M NaOH until slightly basic. After diluting the reaction mixture with dichloromethane (100 ml) the organic phase was partitioned, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (304 mg, 80% yield). HPLC retention time 2.97 min. Mass spectrum (ES+) m/z 383 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH2:27]([NH2:30])[CH:28]=[CH2:29].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:27]([NH:30][C:15]1[C:16]([Cl:18])=[C:17]2[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]2[C:6]2[C:5]([F:25])=[CH:4][C:3]([F:26])=[C:2]([NH2:1])[N:7]=2)=[CH:13][C:14]=1[F:20])[CH:28]=[CH2:29]
Reactant: C=CCN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C=CCNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 40 °C
Reaction time: 63 h
Yield: 60.8 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), allylamine (35 mg) and triethylamine (300 mg) were added to pyridine (400 mg), and the mixture was stirred for 2 hours at 40° C. and for 63 hours at room temperature. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (100 mg) as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[CH2:33][CH2:34]3)[CH:14]=1)=[C:5]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CN2CCN(c3ccccn3)CC2)no1
Yield: 32 %

Procedure:
From 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde and 1-pyridin-2-yl-piperazine according to procedure 24. Yield 32%.