Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5](O)=[O:6].[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:6]
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 3-bromo-4-(4-chlorophenoxy)-benzoic acid (Preparation 29, 19 g, 58 mmol), methanesulfonamide (9.67 g, 102 mmol), EDCI (19.33 g, 101.5 mmol) and DMAP (12.34 g, 101.5 mmol) in DMF (200 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo, diluted with DCM (500 mL), washed with aqueous 1M HCl (3×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 50% petroleum ether in EtOAc to afford the title compound as a white solid (5.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C1(C)C=CC=CC=1.O1CCOCC1.O=[Mn]=O>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:11]([CH:12]=[O:13])=[CH:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)sc1ncc(CO)n12
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)sc1ncc(C=O)n12
Yield: 68.9 %

Procedure:
A suspension of 7-Methyl-imidazo[2,1-b]benzothiazole-3-methanol (Formula K-2) (0.82 g) in hot toluene (100 mL) was diluted with dioxane (10 mL) to effect dissolution of 7-Methyl-imidazo [2,1b]benzothiazole-3-methanol (Formula K-2). The solution was treated with activated MnO2 (1.64 g) and azeotropically distilled for 1.25 hours. The suspension was filtered, the cake was washed with hot ethyl acetate, and the filtrate was evaporated to a crystalline solid (0.69 g). Crystallization from isopropanol gave pure 7-Methyl-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3) (0.56 g), m.p. 170-171°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1)=[O:26]>>[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=3[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=[CH:4][C:3]=2[C:22]#[N:23])[CH:30]=[CH:31][CH:32]=1)(=[O:26])[CH3:24]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COCCOc1ccc2ncc(C#N)c(Cl)c2c1OCCOC
Product: COCCOc1ccc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2c1OCCOC

Procedure:
In the manner of Example 116, 4-Chloro-5,6-bis(2-methoxyethoxy)-3-quinolinecarbonitrile was reacted with 3-aminoacetophenone to give the title compound; recrystallized from ethanol to give off-white solid, mp 250-253 (dec).
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCCC1>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C1CCCN1C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCCN1C(=O)c1ccc(O)cc1

Procedure:
2.0 g. of 1-(p-benzyloxybenzoyl)-2-pyrrolidinone are hydrogenated in 20 ml. of absolute tetrahydrofuran and 20 ml. of absolute methanol over 300 mg. of palladium/carbon (5%) under atmospheric pressure and at room temperature. The catalyst is filtered off, the filtrate is concentrated and the residue is triturated with diethyl ether. After filtration, there is obtained 1-(p-hydroxybenzoyl)-2-pyrrolidinone, having a melting point of 179°-182° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.P(Br)(Br)[Br:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:12][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(C)c(N)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(N)c(Br)n1
Reaction time: 48 h
Yield: 38 %

Procedure:
To a solution of 1.80 g (11.0 mmol) of 2-chloro-4,6-dimethyl-pyridin-3-ylamine (prepared as described in J. M. Klunder et al. J. Med. Chem., 35, 1992, 1887-1897) in toluene (10 ml) was added PBr3 (18 ml). The reaction mixture was stirred for 48 h under reflux. After cooling the reaction mixture, it was poured onto ice, basified with NaOH 2 M solution (400 ml) and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 7:3) to yield 2.31 g (38%) of 2-bromo-4,6-dimethyl-pyridin-3-ylamine containing small amount of 2-chloro-4,6-dimethyl-pyridin-3-ylamine as a yellow oil.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[C:7]([O:11][C:12](=[O:38])[N:13]([C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:23]=2)[CH2:18]1)[CH2:14][CH2:15][CH3:16])([CH3:10])([CH3:9])[CH3:8].O(C(C)(C)C)[Na].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:7]([O:11][C:12](=[O:38])[N:13]([C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([N:4]4[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]4)=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:23]=2)[CH2:18]1)[CH2:14][CH2:15][CH3:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(Br)cc3)ccc2C1
Reactant: F[C@@H]1CCNC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(N4CC[C@@H](F)C4)cc3)ccc2C1
Yield: 47 %

Procedure:
Buchwald coupling reaction using (R)-3-fluoropyrrolidine, Reaction of 0.200 g of [(S)-6-(4-bromo-benzenesulfonylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]-propyl-carbamic acid tert-butyl ester (0.38 mmol), 72 mg of (R)-3-fluoropyrrolidine (0.57 mmol), 51 mg of NaOtC4H9 (1.53 mmol), 39 mg of Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0) (0.04 mmol)), 47 mg of BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (0.08 mmol) in 5 ml tetrahydrofuran at 80° C. for 48 hours yielded 95 mg (47%) of {(S)-6-[4-((R)-3-fluoro-pyrrolidin-1-yl)benzenesulfonylamino]-1,2,3,4-tetrahydro-naphthalen-2-yl}-propyl-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[C:12](=[O:19])[N:13]([CH3:18])[CH2:14][C:15](=O)[NH:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:27])[CH2:24][N+:25]#[C-:26])[CH3:21].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C)C=O>[CH3:18][N:13]1[C:12](=[O:19])[C:11]2=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[CH:8][CH:9]=[C:10]2[N:16]2[CH:26]=[N:25][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:27])=[C:15]2[CH2:14]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCOC(=O)c1cccc2c1C(=O)N(C)CC(=O)N2
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1C(=O)N(C)Cc1c(C(=O)OCC)ncn1-2
Temperature: -20 °C

Procedure:
6-Ethoxycarbonyl-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (10 mmol) was dissolved in 25 ml dry dimethylformamide (DMF). While stirring, K-t-butoxide (12 mmol) was added and the mixture was thereafter cooled to -20° C. A -30° C. cold solution of K-t-butoxide (12 mmol) in dry DMF (15 ml) was charged with isocyano-acetic acid ethylester (12 mmol). This solution was added to the above mentioned solution, and the combined solution was stirred at room temperature for 2 hours. 2 ml of acetic was added, whereafter the solution was evaporated to dryness. The oily residue was subjected to SiO2 -purification with acetone/chloroform (1/3) as eluent. This yielded the title compound as a crystalline powder. M.p. 136.3°-139.9° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([N:24]([CH2:25][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[CH:11]=3)[CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([CH3:33])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CN(Cc2cccc(C)c2)c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-methylbenzaldehyde according to the procedure of Example 66. MS (ESI) m/z 587.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:19]2[CH2:20][O:21]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: BrCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
Potassium carbonate (1.3 g, 9.6 mmol) was added to a mixture of 4-nitrophenol (1.11 g, 8 mmol) and epibromohydrin (1.37 mL, 16 mmol) The mixture was stirred at 100° C. for 18 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na2SO4. Removal of the solvent in vacuo gave an orange residue, which was purified chromatographically on silica eluting with EtOAc/hexanes (1:10, v/v). The product was obtained as a yellow solid (0.8 g, 51%). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.21 (m, 2H), 6.98 (m, 2H), 4.37 (dd, J=2.8 Hz, 11.1 Hz, 1H), 4.00 (dd, J=5.9 Hz, 11.1 Hz, 1H), 3.90 (m, 1H), 2.93 (t, J=4.8 Hz, 1H), 2.77 (dd, J=2.8 Hz, 4.8 Hz, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)=[CH:7][CH2:6]1>ClCCl>[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([Cl:3])=[O:20])=[CH:17][CH:16]=2)=[CH:7][CH2:6]1
Reactant: O=C(O)c1ccc(C2=CCOc3ccccc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C2=CCOc3ccccc32)cc1
Reaction time: 4 h
Yield: 99 %

Procedure:
Thionyl chloride (2 mL) was added to a suspension of 4-(2H-chromen-4-yl)benzoic acid from reaction 34c (0.415 g, 1.6 mmol) in dichloromethane (10 mL) at room temperature. The reaction was stirred for 4 h, concentrated in vacuo to give 4-(2H-chromen-4-yl)benzoyl chloride (0.445 g, 99%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:9].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>O1CCCC1>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:9][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12]
Reactant: O=S1(=O)CCCO1
Reactant: CC1CCCC(N)C1C
Solvent: C1CCOC1
Product: CC1CCCC(NCCCS(=O)(=O)O)C1C
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethylcyclohexylamine (10.0 g, 79.0 mmol) in tetrahydrofuran (60 mL) was slowly added a solution of 1,3-propane sultone (9.3 g, 75.0 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with THF (50 mL) and acetone (50 mL). The solid was dissolved in 25% EtOH/water (150 mL), and treated with Dowex 50WX8 resin (15 g). The suspension stirred at room temperature for 5 minutes. The resin was removed by filtration. The filtrate was concentrated to dryness under reduced pressure; and the solid residue was suspended in acetone (100 mL). The solid material was collected by filtration, and dried in vacuo; affording compound DK (7.4 g, 43%). 1H NMR (D2O, 500 MHz) δ ppm 3.29 (m, 0.5H), 3.09 (m, 2H), 2.88 (t, 2H, J=7.3 Hz), 2.80 (m, 0.5H), 1.99 (m, 3H), 1.40 (m, 7H), 0.81 (m, 6H). 13C NMR (D2O, 125 MHz) δ ppm 62.85, 61.56, 59.88, 58.22, 48.26, 48.15, 44.29, 43.84, 43.59, 42.65, 42.01, 41.03, 37.34, 36.12, 34.73, 34.45, 33.88, 33.64, 29.39, 28.00, 26.50, 24.25, 24.02, 23.64, 22.42, 21.55, 21.45, 21.35, 19.38, 19.13, 18.82, 18.40, 14.38, 13.39, 4.59. ES-MS 248 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:4]=1[CH:5]=[N:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:4]=1[CH2:5][NH:6][CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: COc1ccc(OC)c(C=NCC(OC)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OC)c(CNCC(OC)OC)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Amine 11d (10.64 g, 0.042 mol) was dissolved in ethanol (100 mL) and NaBH4 (2.6 g) was added and the reaction mixture was stirred at 80-90° C. After 3 h the TLC indicated the absence of the starting material. The organic layer was washed with water (2×200 mL), brine (200 mL), dried (Na2SO4) and concentrated to provide a colorless oil (10.71 g, 100%). 1H NMR (300 MHz CDCl3) 6.79-6.67 (m, 3H), 4.43 (t, J=5.7 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.68 (d, J=2.7 Hz, 2H), 3.28 (s, 6H), 2.7 (s, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>CCOCC.C1OCCOCCOCCOCCOCCOC1>[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:14])[CH3:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1cc[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Pyrrole (2.9 ml, 42 mmol) was added dropwise with stirring at room temperature to a suspension of potassium tert-butoxide (4.66 g, 42 mmol) and 18-crown-6 (0.2 g, 0.76 mmol) in ether (300 ml). After 1 hour tri-isopropylsilyl chloride (8.Og, 42 mmol) was added dropwise, and then the reaction mixture was stirred for 16 hours, and filtered. The residue was washed with ether and the combined filtrate and washings were washed with brine, then dried and concentrated to give N-tri-isopropylsilylpyrrole (8.0 g, 86% yield) as a clear oil, 1H nmr : delta 1.04 (18H, d), 1.38 (3H, m), 6.22 (2H, m), 6.72 (2H, m) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45])#[N:40]>C(Cl)Cl>[C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:45])#[N:40]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)N2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (0.318 g) in CH2Cl2 (15 mL) containing Et3N (79 mg) was added dropwise 3-cyano-benzoyl chloride (0.129 g) and the mixture was stirred at room temperature for 1 hour. The solution was then washed with water, with brine, dried over Na2SO4, filtered and evaporated. The residue was then purified by flash chromatography eluting with CH2Cl2/AcOEt (80/20) and the solid obtained was recrystallized from AcOEt to give the title compound (0.29 g) as white crystals.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)=O.C([NH:26][NH2:27])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C(O)(=O)C.C(O)C>[C:11]([C:9]1[O:10][C:6]([C:4]2[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:27][N:26]=2)=[CH:7][CH:8]=1)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2F)o1
Reactant: NNC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1

Procedure:
2.5 g (11 mmol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid, 3.28 g (24 mmol) of benzhydrazide and 2 drops of glacial acetic acid in 50 ml of ethanol were heated under reflux for 10 h. The mixture was subsequently concentrated using a rotary evaporator and the residue was taken up in water, made alkaline using 2 N NaHCO3 solution and extracted with ethyl acetate. The aqueous phase was made acidic using 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated using a rotary evaporator. The residue was dissolved in 25 ml of THF, 2.74 g (24.2 mmol) of potassium tert-butoxide were added and the mixture was stirred at reflux temperature for 1.5 h. After cooling, the mixture was concentrated using a rotary evaporator and the residue was taken up in 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The precipitate that resulted when the aqueous phase was acidified was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 40° C. This gave 1.88 g (75%) of the title compound. m.p.: 205° C. (decomp).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH:16]([CH3:18])[CH3:17].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH:16]([CH3:18])[CH3:17])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
20% palladium hydroxide (wet, 60 mg) was added to a solution of tert-butyl cis(±)-4-(benzylamino)-3-isopropoxypiperidine-1-carboxylate obtained in Example (147d) (120 mg, 0.345 mmol) in methanol (1.2 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the resulting residue, and the organic substance was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 74 mg of tert-butyl cis(±)-4-amino-3-isopropoxypiperidine-1-carboxylate as a colorless oily substance (83%). The resulting amine was dissolved in DMF (1 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 54 mg, 0.29 mmol) was added, and the mixture was cooled in an ice water bath. 1-Hydroxybenzotriazole (44 mg, 0.31 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (60 mg, 0.31 mmol) were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, sequentially washed with brine, water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol) to obtain 60.6 mg of the title compound as a colorless solid (50%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH:37]=[CH2:36]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: C=CCBr
Product: C=CCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and m-anisidine (2.96 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([N:22]([CH2:24][C@@H:25]4[CH2:30][O:29][CH2:28][CH2:27][O:26]4)[CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][C@H:25]1[CH2:24][N:22]([CH3:23])[S:19]([NH:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1)(=[O:21])=[O:20]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(C[C@@H]1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: CN(C)C=O
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 135 °C

Procedure:
N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-[(2R) 1,4-dioxan-2-ylmethyl]-N-methylsulfamide (0.500 g, 1.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.692 g, 3.33 mmol), Pd2(dba)3 (0.051 g, 0.056 mmol), (tBu3)PBF4 (0.032 g, 0.11 mmol) and potassium fluoride (0.212 g, 3.66 mmol) were combined in a dry tube. 5 mL dry DMF was added and argon was bubbled through the solution for five minutes. The tube was sealed and heated in the Biotage Initiator series microwave to 135° C. for 20 minutes. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and brine. The organic layer was dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by silica chromatography (0-100% ethyl acetate/hexanes gradient followed by 0-10% methanol/dichloromethane gradient) to afford the crude compound. The crude material was crystallized from a mixture of 10 mL methanol, 40 mL dichloromethane, and 70 mL hexanes to afford the title compound. 1H NMR (600 MHz, D6-DMSO) δ 10.52 (s, 1H); 9.20 (d, 1H); 8.55 (d, 1H); 8.45 (s, 1H); 8.13 (s, 1H); 7.95 (d, 1H); 7.75 (d, 1H); 7.55 (d, 1H); 7.32 (d, 1H); 7.22 (d, 1H); 3.88 (s, 3H); 3.64-3.60 (m, 2H); 3.58-3.54 (m, 1H); 3.54-3.50 (m, 1H); 3.44-3.40 (m, 1H); 3.38-3.34 (m, 1H); 3.14-3.10 (m, 3H); 2.77 (s, 3H). LRMS (APCI) calc'd for (C24H26N5O5S) [M+H]+, 496.2; found, 496.2.